CN116947885A - Condensed pyridone compound, preparation method and application thereof - Google Patents

Abstract

The invention discloses a condensed pyridone compound, a preparation method and application thereof, in particular to a compound shown in a formula (I-B)The compounds, optical isomers and pharmaceutically acceptable salts thereof, and the use of the compounds as KRAS inhibitors.

Description

Condensed pyridone compound and preparation method and application thereof

The present invention claims the following priority:

CN201910892032.X, application date is September 20, 2019,

CN201911129688.2, application date is November 18, 2019,

CN201911157939.8, application date is November 22, 2019,

CN202010054188.3, application date is January 17, 2020,

CN202010102546.3, application date is February 19, 2020,

CN202010230303.8, application date is March 27, 2020,

CN202010306926.9, application date is April 17, 2020,

CN202010367694.8, application date is April 30, 2020,

CN202010967317.8, application date is September 15, 2020.

Technical Field

The present invention relates to a compound represented by formula (I-B), an optical isomer thereof and a pharmaceutically acceptable salt thereof, and application of the compound as a KRAS inhibitor.

Background Art

About 30% of cancer patients have RAS gene mutations. In the study of cancer genes, scientists discovered more than 20 years ago that RAS gene is a key gene for cancers including lung cancer, colorectal cancer and pancreatic cancer.

In the United States, the three cancers with the highest mortality rates (pancreatic cancer, colorectal cancer, and lung cancer) also happen to be the three cancers with the most common RAS mutations, accounting for 95%, 52%, and 31% of the patients with these three cancers, respectively. In pancreatic cancer, colorectal cancer, and lung cancer, KRAS mutations account for the absolute majority, while NRAS mutations are more common in melanoma and acute myeloid leukemia, and HRAS mutations are more common in bladder cancer and head and neck cancer.

The mutation rate of the KRAS gene in Asian populations is 10–15%. KRAS is mutated in many cancers and is one of the major oncogenes. KRAS mutant tumors are the most potentially targetable molecular subtype of non-small cell lung cancer (NSCLC), with a mutation rate of approximately 15%-25% in non-small cell lung cancer (NSCLC). In cases of NSCLC, KRAS mutations mainly occur in codons 12 and 13. The most common codon variation, which accounts for approximately 39% of KRAS mutant NSCLCs, is the KRAS-G12C mutation.

In lung adenocarcinoma, the probability of KRAS gene positivity accounts for 1/5-1/4, second only to the probability of EGFR positive mutation. The lack of targeted inhibitors makes it very difficult for KRAS-positive non-small cell lung cancer patients to be treated and to be diagnosed. The 2013 NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer clearly states that lung cancer patients must undergo KRAS gene testing before receiving EGFR-TKI treatment, and decide whether to use EGFR-TKI targeted drugs as clinical treatment measures based on the test results. If the KRAS gene is mutated, it is not recommended that patients use EGFR-TKI for molecular targeted therapy.

According to the Thomson Reuters Competitive Intelligence Drug Database (Cortellis For CI), there are currently 162 drugs directly related to RAS genes/proteins (data query time August 18, 2016), of which there are 18 KRAS small molecule drugs, including 10 KRAS GTPase inhibitors, 4 KRAS gene inhibitors, 2 KRAS GTPase regulators and 2 KRAS gene regulators; there is currently one drug of this type under clinical research. In addition, the first KRAS inhibitor, Antujian, has entered the US FDA Phase II clinical trial, and AstraZeneca's inhibitor selumetinib for the KRAS downstream pathway MEK is also undergoing Phase II clinical trials. KRAS mutation is the most important tumor driver gene. This part of the mutation cases accounts for a certain proportion in pancreatic cancer, lung cancer and colorectal gastric cancer. There is currently no specific targeted drug that acts on this target. Therefore, this project has important medical research value and clinical application value, and has greater medical value for the Chinese people. Develop a small molecule drug for KRAS-G12C, whose molecular mechanism has been basically elucidated, and whose molecular structure and pharmacodynamic effects have been verified under existing experimental conditions. It has high activity characteristics and the possibility of becoming a drug.

Summary of the invention

In the first aspect of the present invention, the present invention provides a compound represented by formula (I-B), an optical isomer thereof and a pharmaceutically acceptable salt thereof,

in,

R ₁ and R ₂ are independently selected from H, halogen and C _1-6 alkyl, and the C _1-6 alkyl is optionally substituted by 1, 2 or 3 R;

R ₃ is selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 heteroalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl-O- and C _3-6 cycloalkyl-O-, wherein the C _1-6 alkyl, C _1-6 heteroalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl-O- or C _3-6 cycloalkyl-O- is optionally substituted with 1, 2 or 3 R;

R ₄ is independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C 1-6 heteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl, _3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;

R ₅ is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl-C _1-3 alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl-C _1-3 alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;

L ₁ is selected from -C(=O)-, -S(=O)- and -S(=O) ₂ -;

_R6 is selected from H, CN, _C1-6 alkyl, _C1-6 alkyl-S(=O) _2- , 3-6 membered heterocycloalkyl, _-C1-6 alkyl-3-6 membered heterocycloalkyl and _C3-6 cycloalkyl-C(=O)-, wherein the _C1-6 alkyl, _C1-6 alkyl-S(=O) _2- , 3-6 membered heterocycloalkyl, _-C1-6 alkyl-3-6 membered heterocycloalkyl or _C3-6 cycloalkyl-C(=O)- is optionally substituted by 1, 2 or 3 R;

R ₇ is independently selected from H, halogen, OH, NH ₂ , CN, -C(＝O)-OH, C _1-6 alkyl-OC(＝O)-, -C(＝O)-NH ₂ , C _1-6 alkyl, C _1-6 heteroalkyl and -C _1-6 alkyl-3～6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _1-6 heteroalkylC _1-6 alkyl-OC(＝O)- or -C _1-6 alkyl-3～6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;

T ₁ and T ₂ are independently selected from N and -C(R ₈ )-;

R ₈ is selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C 1-6 heteroalkyl, C _3-6 cycloalkyl or _3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;

R ₉ is selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl and C _1-6 heteroalkyl, wherein the C _1-6 alkyl or C _1-6 heteroalkyl is optionally substituted with 1, 2 or 3 R;

R ₁₀ is selected from H, halogen, CN, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylamino, wherein the C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkylamino is optionally substituted by 1, 2 or 3 R;

R is independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 heterocycloalkyl, C _3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, C _3-6 cycloalkyl-O- and 5- to 6-membered heterocycloalkyl-O-, wherein the C _1-6 alkyl, C _1-6 heterocycloalkyl, C _3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, C _3-6 cycloalkyl-O- or 5- to 6-membered heterocycloalkyl-O- is optionally substituted with 1, 2 or 3 R's;

R' is selected from F, Cl, Br, I, OH, _NH2 and _CH3 ;

Ring A is independently selected from C _6-10 aryl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl;

n is selected from 0, 1, 2, 3 or 4;

m is selected from 0, 1, 2, 3 or 4;

D ₁ is selected from O;

Y is selected from N, CH or C;

for And when for When R ₂ and R ₁₀ do not exist;

for when middle for When X ₁ and X ₂ are independently selected from -N＝, -C(R ₇ )＝ and -C(R ₇ ) ₂ -C(R ₇ )＝;

when middle for when X ₁ and X ₂ are independently selected from a single bond, -O-, -S-, S(=O), S(=O) ₂ , -N(R ₆ )-, -C(=O)-, -C(R ₇ ) ₂ - and -C(R ₇ ) ₂ -C(R ₇ ) ₂ -;

And, Y cannot connect two When the bond between Y and R ₉ is When , R ₉ does not exist;

The above 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl or C _1-6 heterocycloalkyl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) ₂ - and N.

In another aspect of the present invention, the present invention also provides a compound represented by formula (I-A), an optical isomer thereof and a pharmaceutically acceptable salt thereof,

in,

R ₁ and R ₂ are independently selected from H, halogen and C _1-6 alkyl, and the C _1-6 alkyl is optionally substituted by 1, 2 or 3 R;

R ₃ is selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 heteroalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl-O- and C _3-6 cycloalkyl-O-, wherein the C _1-6 alkyl, C _1-6 heteroalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl-O- or C _3-6 cycloalkyl-O- is optionally substituted with 1, 2 or 3 R;

R ₄ is independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C 1-6 heteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl, _3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl is optionally substituted by 1, ₂ or 3 R;

R ₅ is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl-C _1-3 alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl-C _1-3 alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;

L ₁ is selected from -C(=O)-, -S(=O)- and -S(=O) ₂ -;

_R6 is selected from H, CN, _C1-6 alkyl, _C1-6 alkyl-S(=O) _2- , 3-6 membered heterocycloalkyl, _-C1-6 alkyl-3-6 membered heterocycloalkyl and _C3-6 cycloalkyl-C(=O)-, wherein the _C1-6 alkyl, _C1-6 alkyl-S(=O) _2- , 3-6 membered heterocycloalkyl, _-C1-6 alkyl-3-6 membered heterocycloalkyl or _C3-6 cycloalkyl-C(=O)- is optionally substituted by 1, 2 or 3 R;

R ₇ is independently selected from H, halogen, OH, NH ₂ , CN, -C(＝O)OH, C _1-6 alkyl-OC(＝O)-, -C(＝O)-NH ₂ , C _1-6 alkyl, C _1-6 heteroalkyl and -C _1-6 alkyl-3～6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C 1-6 heteroalkyl, C _1-6 alkyl- _OC (＝O)- or -C _1-6 alkyl-3～6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;

T ₁ and T ₂ are independently selected from N and -C(R ₈ )-;

R ₈ is selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C 1-6 heteroalkyl, C _3-6 cycloalkyl or _3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;

R is independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 heterocycloalkyl, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C _3-6 cycloalkyl-O- and _5-6 membered heterocycloalkyl-O-, wherein the C _1-6 alkyl, C _{1-6 heterocycloalkyl, C 3-6 cycloalkyl} , 5-6 membered heterocycloalkyl, C _3-6 cycloalkyl-O- or 5-6 membered heterocycloalkyl-O- is optionally substituted with 1, 2 or 3 R';R' is selected from F, Cl, Br, I, OH, NH ₂ and CH ₃ ;

Ring A is independently selected from C _6-10 aryl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl;

n is selected from 0, 1, 2, 3 or 4;

for And when for When , R ₂ does not exist;

for or;

when middle for When X ₁ and X ₂ are independently selected from -N＝, -C(R ₇ )＝ and -C(R ₇ ) ₂ -C(R ₇ )＝;

when middle for when X ₁ and X ₂ are independently selected from a single bond, -O-, -S-, S(=O), S(=O) ₂ , -N(R ₆ )-, -C(=O)-, -C(R ₇ ) ₂ - and -C(R ₇ ) ₂ -C(R ₇ ) ₂ -;

The above 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl or C _1-6 heterocycloalkyl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) ₂ - and N.

In some embodiments of the present invention, the above-mentioned compound, its optical isomers and pharmaceutically acceptable salts thereof are selected from

in,

X ₁ and X ₂ are each independently selected from a single bond, -O-, -S-, S(=O), S(=O) ₂ , -N(R ₆ )-, -C(=O)-, -C(R ₇ ) ₂ - and -C(R ₇ ) ₂ -C(R ₇ ) ₂ -; R ₁ , R _{2 , R 3 ,} R ₄ , R ₅ , L ₁ , R ₆ , R ₇ , T ₁ , T ₂ , Ring A and n are as defined above.

In some embodiments of the present invention, the above R is independently selected from H, halogen, OH, NH ₂ , CN, C _1-3 alkyl, C _1-3 alkoxy, C _{1-3 alkylthio, C 1-3} alkylamino, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C _3-6 cycloalkyl-O- and -5-6 membered heterocycloalkyl-O-, wherein the C _1-3 alkyl, C _1-3 alkoxy, _{C 1-3} alkylthio, C _{1-3 alkylamino, C 3-6 cycloalkyl} , 5-6 membered heterocycloalkyl, C _3-6 cycloalkyl-O- or 5-6 membered heterocycloalkyl-O- are optionally substituted with 1, 2 or 3 R's, and the other variables are as defined herein.

In some embodiments of the present invention, the above R is independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, Me, CH ₂ CH ₃ ,

Other variables are as defined herein.

In some embodiments of the present invention, the above R ₁ and R ₂ are independently selected from H, F, Me, CF ₃ , Other variables are as defined herein.

In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined herein.

In some embodiments of the present invention, the above _R3 is selected from H, halogen, OH, _NH2 , CN, _C1-3 alkyl, C1-3 alkoxy, C1-3 alkylamino, C1-3 alkylthio, 3-6 membered heterocycloalkyl, _C3-6 cycloalkyl, _3-6 membered heterocycloalkyl-O- and _C3-6 cycloalkyl-O-, and the _C1-3 alkyl, _{C1-3 alkoxy} , _C1-3 alkylamino, _C1-3 alkylthio, _3-6 membered heterocycloalkyl, _C3-6 cycloalkyl, 3-6 membered heterocycloalkyl-O- or _C3-6 cycloalkyl-O- are optionally substituted with ₁ , 2 or 3 R, and other variables are as defined in the present invention.

In some embodiments of the present invention, the above R ₃ is selected from H, F, Cl, Br, I, OH, NH ₂ , CN, Me, CF ₃ , Other variables are as defined herein.

In some embodiments of the present invention, the above R ₄ is independently selected from H, halogen, OH, NH ₂ , CN, C _1-3 alkyl, C _1-3 alkoxy, C _{1-3 alkylamino, C 1-3} alkylthio, C _3-6 cycloalkyl, _3-6 membered heterocycloalkyl, phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl, _isothiazolyl , oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, _{1,2,3 -} triazolyl, _1,2,4 -triazolyl, benzofuranyl, benzothienyl and indolyl. _3-6 -membered cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl or indolyl are optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

In some embodiments of the present invention, the above R ₄ is selected from H, F, Cl, Br, I, OH, NH ₂ , CN, Me, CF ₃ , Other variables are as defined herein.

In some embodiments of the present invention, the ring A is selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, 1H-benzo[d]imidazolyl, benzopyrazolyl, purinyl, quinolyl, isoquinolyl, isoquinolin-1(2H)-onyl, isoindolyl-1-onyl, benzo[d]oxazol-2(H)-onyl, benzo[d]oxazol-2(3H)-onyl, H-benzo[d][1,2,3]triazolyl, 1H-pyrazolo[3,4-b]pyridinyl, benzo[d]thiazolyl and 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, the phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, 1H-benzo[d]imidazolyl, benzopyrazolyl, purinyl, quinolyl, isoquinolyl, isoquinolinyl, isoquinolin-1(2H)- Keto, isoindolin-1-on, benzo[d]oxazol-2(H)-on, benzo[d]oxazol-2(3H)-on, H-benzo[d][1,2,3]triazolyl, 1H-pyrazolo[3,4-b]pyridinyl, benzo[d]thiazolyl or 1,3-dihydro-2H-benzo[d]imidazol-2-on is optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined herein.

In some embodiments of the present invention, _R5 is selected from H, _C1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, 5-6 membered heterocycloalkyl-C _1-3 alkyl-, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, purinyl, quinolyl, isoquinolyl, isoquinolin-1(2H)-onyl, isoindolyl-1-onyl, benzo[d]oxazol-2(H)-onyl and 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, the C _1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, 5-6 membered heterocycloalkyl-C _1-3 alkyl-, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, purinyl, quinolinyl, isoquinolinyl, isoquinolin-1(2H)-onyl, isoindolin-1-onyl, benzo[d]oxazol-2(H)-onyl or 1,3-dihydro-2H-benzo[d]imidazol-2-onyl is optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

In some embodiments of the present invention, the above R ₅ is selected from H, Me,

Other variables are as defined herein.

In some embodiments of the present invention, the above _R7 is independently selected from H, halogen, OH, _NH2 , CN, _C1-3 alkyl, _C1-3 alkyl-OC(＝O)-, -C(＝O) _-NH2 , _C1-3 alkoxy, _C1-3 alkylamino, _C1-3 alkylthio and _-C1-3 alkyl-3 to 6-membered heterocycloalkyl, and the _C1-3 alkyl, _C1-3 alkyl-OC(＝O)-, -C(＝O) _-NH2 , _C1-3 alkoxy, _C1-3 alkylamino, _C1-3 alkylthio or _-C1-3 alkyl-3 to 6-membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R, and other variables are as defined in the present invention.

In some embodiments of the present invention, the above R ₇ is independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, Me, CF ₃ ,

Other variables are as defined herein.

In some embodiments of the present invention, the above _R6 is independently selected from H, CN, _C1-3 alkyl, _C1-3 alkyl-S(＝O) _2- , 3-6 membered heterocycloalkyl, _-C1-3 alkyl- _3-6 membered heterocycloalkyl and C3-6 cycloalkyl-C(＝O)-, and the _C1-3 alkyl, _C1-3 alkyl-S(＝O) _2- , 3-6 membered heterocycloalkyl, _-C1-3 alkyl 3-6 membered heterocycloalkyl or _C3-6 cycloalkyl-C(＝O)- is optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.

In some embodiments of the present invention, the above R ₆ is independently selected from H, CN, Me, CF ₃ ,

Other variables are as defined herein.

In some embodiments of the present invention, X ₁ and X ₂ are independently selected from a single bond, CH ₂ , CH ₂ CH ₂ , C(═O), O, S, NH, N(CH ₃ ), S(═O), S(═O) ₂ , Other variables are as defined herein.

In some embodiments of the present invention, the above _R8 is selected from H, halogen, OH, _NH2 , CN, _C1-3 alkyl, _C1-3 alkoxy, C1-3 alkylamino and _C1-3 alkylthio, wherein the _C1-3 alkyl, _C1-3 alkoxy, _C1-3 alkylamino or _{C1-3 alkylthio} is optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.

In some embodiments of the present invention, the above R ₈ is selected from H, F, Cl, Br, I, OH, NH ₂ , CN, Me, CF ₃ , Other variables are as defined herein.

In some embodiments of the present invention, the above structural unit Selected from

Other variables are as defined herein.

In yet another aspect of the present invention, the present invention also provides the following compounds, their optical isomers and pharmaceutically acceptable salts thereof:

In another aspect of the present invention, the present invention also provides a pharmaceutical composition, which contains the compound as described above, its optical isomers and pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

In another aspect of the present invention, the present invention also proposes the use of the aforementioned compound, its optical isomers and pharmaceutically acceptable salts thereof or the aforementioned pharmaceutical composition in the preparation of a drug for preventing and/or treating a KRAS-G12C-related disease.

In some embodiments of the present invention, the above-mentioned KRAS-G12C-related disease is selected from non-small cell lung cancer, colon cancer and pancreatic cancer.

Definition and Description

Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases. When the compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, etc.; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.

Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

A hyphen ("-") that is not between two letters or symbols indicates the point of attachment of a substituent. For example, _C1-6 alkylcarbonyl- refers to a _C1-6 alkyl group that is attached to the rest of the molecule via a carbonyl group. However, when the point of attachment of a substituent is obvious to one skilled in the art, for example, a halogen substituent, the "-" may be omitted.

When the group valence bond is marked with a dotted line When, for example, In the molecule, the wavy line indicates the point of attachment of the group to the rest of the molecule.

The compounds of the present invention may exist in specific geometric or stereoisomer or optical isomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability of a ring to rotate freely about double bonds or single bonds of ring carbon atoms.

Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

Unless otherwise specified, the key is a solid wedge. and dotted wedge key Indicates the absolute configuration of a stereocenter.

The compounds of the present invention may exist in specific forms. Unless otherwise indicated, the term "tautomer" or "tautomeric form" means that at room temperature, different functional group isomers are in dynamic equilibrium and can quickly convert to each other. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be achieved. For example, proton tautomers (proton tautomers) (also called prototropic tautomers) include interconversions carried out by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence isomers (valencetautomers) include interconversions carried out by the reorganization of some bonding electrons. Among them, a specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one.

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound. For example, compounds may be labeled with radioactive isotopes, such as tritium ( ^3H ), iodine-125 ( ^125I ) or C-14 ( ^14C ). For another example, deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention. "Optional" or "optionally" means that the event or situation described subsequently may but does not necessarily occur, and the description includes situations in which the event or situation occurs and situations in which the event or situation does not occur.

Stereochemical definitions and conventions may be followed in S. P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that are optically inactive.

The racemic mixture can be used in its own form or resolved into individual isomers. Stereochemically pure compounds or mixtures enriched in one or more isomers can be obtained by resolution. Methods for separating isomers are well known (see Allinger N.L. and Eliel E.L., "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods, such as chromatography using chiral adsorbents. Individual isomers in chiral form can be prepared from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture by forming diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts, then freeing one or both of the resolved bases, and optionally repeating this process to obtain one or both isomers that are substantially free of the other isomer, i.e., the desired stereoisomers having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight. Alternatively, as is well known to those skilled in the art, the racemates can be covalently linked to chiral compounds (auxiliaries) to obtain diastereomers.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be arbitrary on the basis of chemical achievable.

When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.

When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected, such as When L ₃ represents a single bond, it means that the structure is actually

When the substituent is listed without indicating the atom through which it is connected to the substituted group, such substituent can be bonded through any atom thereof. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The connecting group L is at this time You can connect benzene rings and cyclohexane in the same direction as reading from left to right to form You can also connect benzene rings and cyclohexane in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, "5-7 membered ring" refers to a "ring" having 5-7 atoms arranged around it.

Unless otherwise specified, the term "C _1-6 alkyl" is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C _1-6 alkyl includes C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ and C ₅ alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C _1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

Unless otherwise specified, the term "C _1-3 alkyl" is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C _1-3 alkyl group includes C _1-2 and C _2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C _1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

The term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- and -S(=O)N(H)-. In some embodiments, the heteroalkyl is C _1-6 heteroalkyl; in other embodiments, the heteroalkyl is C _1-3 heteroalkyl. The heteroatom or heteroatom group may be placed at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule, but the terms "alkoxy,""alkylamino," and "alkylthio" (or thioalkoxy) are conventional expressions and refer to those alkyl groups attached to the remainder of the molecule through an oxygen, amino or sulfur atom, respectively. Examples of heteroalkyl groups include, but are not limited to _{, -OCH3} , _{-OCH2CH3 , -OCH2CH2CH3} , _-OCH2 ( _{CH3 ) 2} , -CH2 _{- CH2} -O- _CH3 , _-NHCH3 , -N(CH3 _{) 2} , _-NHCH2CH3 , -N( _CH3 )( _CH2CH3 ), -CH2- _CH2 - _NH - _CH3 , _-CH2 - _CH2 -N( _CH3 ) _-CH3 , _-SCH3 , -SCH2CH3, _-SCH2CH2CH3 , _-SCH2 ( _CH3 ) ₂ , -CH2 _{- S - CH2 -CH3 , -CH2 - CH2} , -S(= _O ) _-CH3 , _{-CH2 - CH2} -S(=O) ₂ -CH ₃ , and Up to two heteroatoms may be consecutive, for example -CH ₂ -NH-OCH ₃ .

Unless otherwise specified, the term "C _1-6 alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through an oxygen atom. The C _1-6 alkoxy includes C _1-4 , C _1-3 , C 1-2, C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ and C ₃ alkoxy, etc. Examples of C _1-6 alkoxy include, but are _not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentyl and neopentyl), hexyl and the like.

Unless otherwise specified, the term "C _1-3 alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through an oxygen atom. The C _1-3 alkoxy includes C _1-2 , C _2-3 , C ₃ and C ₂ alkoxy, etc. Examples of C _1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

Unless otherwise specified, the term "C _1-6 alkylamino" refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an amino group. The C _1-6 alkylamino group includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ , C ₃ and C ₂ alkylamino groups, etc. Examples of C _1-6 alkylamino groups include, but are not limited to, -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ )CH ₂ CH ₃ , -N(CH ₂ CH ₃ )(CH ₂ CH ₃ ), -NHCH ₂ CH ₂ CH ₃ , -NHCH ₂ (CH ₃ ) ₂ , -NHCH ₂ CH ₂ CH ₂ CH ₃ , and the like.

Unless otherwise specified, the term "C _1-3 alkylamino" refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group. The C _1-3 alkylamino group includes C _1-2 , C ₃ and C ₂ alkylamino groups, etc. Examples of C _1-3 alkylamino groups include, but are not limited to, -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ )CH ₂ CH ₃ , -NHCH ₂ CH ₂ CH ₃ , -NHCH ₂ (CH ₃ ) ₂ , and the like.

Unless otherwise specified, the term "C _1-6 alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through a sulfur atom. The C _1-6 alkylthio includes C _1-4 , C _1-3 , C _1-2 , C _{2-6, C 2-4} , C ₆ , C ₅ , C ₄ , C ₃ and C ₂ alkylthio, etc. Examples of C _1-6 alkylthio include, but are not limited to, -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH ₂ (CH ₃ ) _{2 ,} and the like.

Unless otherwise specified, the term "C _1-3 alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through a sulfur atom. The C _1-3 alkylthio group includes C _1-3 , C _1-2 and C ₃ alkylthio groups, etc. Examples of C _1-3 alkylthio groups include, but are not limited to, -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH ₂ (CH ₃ ) ₂ , etc.

Unless otherwise specified, "C _3-6 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C _3-6 cycloalkyl includes C _3-5 , C _4-5 and C _5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent. Examples of C _3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

Unless otherwise specified, the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings. In addition, with respect to the "3-8 membered heterocycloalkyl", heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule. The 3-8 membered heterocycloalkyl includes 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 3-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.

Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings. In addition, with respect to the "3-6 membered heterocycloalkyl", heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

Unless otherwise specified, the terms "C _6-10 aromatic ring" and "C _6-10 aryl" of the present invention can be used interchangeably. The term "C _6-10 aromatic ring" or "C _6-10 aryl" means a cyclic hydrocarbon group composed of 6 to 10 carbon atoms with a conjugated π electron system, which can be a monocyclic ring, a fused bicyclic ring or a fused tricyclic ring system, wherein each ring is aromatic. It can be monovalent, divalent or polyvalent. C _6-10 aryl includes C _6-9 , C ₉ , C ₁₀ and C ₆ aryl, etc. Examples of C _6-10 aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" of the present invention can be used interchangeably. The term "5-10 membered heteroaryl" refers to a cyclic group consisting of 5 to 10 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). The 5-10 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom. The 5-10 membered heteroaryl includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl, etc. Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4- thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.), or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably. The term "5-6 membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). The 5-6 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

Unless otherwise specified, "benzo 5-6 membered heterocycloalkyl" means a bicyclic structure formed by the combination of phenyl and heterocyclic ring and 5-6 membered heterocycloalkyl, and the substituent can be connected to other structures through the benzene ring or the 5-6 membered heterocycloalkyl ring. Examples of the benzo 5-6 membered heterocycloalkyl include but are not limited to wait.

Unless otherwise specified, "5-6 membered heteroaryl and 5-6 membered heterocycloalkyl" means a bicyclic structure formed by the combination of a 5-6 membered heteroaryl and a heterocycle and a 5-6 membered heterocycloalkyl, and the substituent can be connected to other structures through a 5-6 membered heteroaryl or a 5-6 membered heterocycloalkyl ring. Examples of the benzo 5-6 membered heterocycloalkyl include but are not limited to wait.

Unless otherwise specified, Cn _-n+m or _Cn - _Cn+m includes any specific case of n to n+m carbon atoms, for example, _C1-12 includes _C1 , _C2 , C3, _C4 , _C5 , _C6 , _C7 , _C8 , _C9 , _C10 , _C11 , and _C12 , and also includes any range from n to n+m, for example, _C1-12 includes _C1-3 , C1-6, _C1-9 , _{C3-6 , C3-9} , _C3-12 , _C6-9 , _C6-12 , _and C13. _9-12, etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.

As used herein, the term "treatment" refers to the administration of one or more drug substances, particularly compounds of formula (I) and/or pharmaceutically acceptable salts thereof, to an individual suffering from a disease or symptoms of the disease, in order to cure, alleviate, mitigate, alter, cure, improve, ameliorate or affect the disease or symptoms of the disease. As used herein, the term "prevention" refers to the administration of one or more drug substances, particularly compounds of formula (I) and/or pharmaceutically acceptable salts thereof, to an individual with a physique susceptible to the disease, in order to prevent the individual from suffering from the disease. When referring to a chemical reaction, the terms "treating", "contacting" and "reacting" refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and/or desired product. It should be understood that the reaction that produces the indicated and/or desired product may not necessarily result directly from the combination of the two reagents initially added, that is, there may be one or more intermediates generated in the mixture, which ultimately lead to the formation of the indicated and/or desired product.

The term "effective amount" as used herein refers to an amount that is generally sufficient to produce a beneficial effect on an individual. The effective amount of the compound of the present invention can be determined by conventional methods (e.g., modeling, dose escalation studies or clinical trials) in combination with conventional influencing factors (e.g., mode of administration, pharmacokinetics of the compound, severity and course of the disease, individual medical history, individual health status, individual response to the drug, etc.).

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

The solvent used in the present invention can be obtained from commercial sources. The present invention uses the following abbreviations: CDCl ₃ represents deuterated chloroform; CD ₃ OD represents deuterated methanol; DMSO-d ₆ represents deuterated dimethyl sulfoxide; TBS represents tert-butyl dimethylsilyl.

Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a graph showing the relationship between the number of days of NCI-H358 cell inoculation and body weight changes after administration of Example Compound 29B according to an example of the present invention.

FIG. 2 is a graph showing the relationship between the number of days of NCI-H358 cell inoculation and tumor volume after administration of Example Compound 29B according to an example of the present invention.

DETAILED DESCRIPTION

The present application is described in detail below by way of examples, but it is not intended that there is any adverse limitation to the present application. The present application has been described in detail herein, and its specific embodiments are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

Example 1: Preparation of Compound 1

Step 1: Preparation of compound 1-2

The raw material 1-1 (2.00 g, 9.57 mmol) was dissolved in thionyl chloride (10 mL), heated to 80 ° C and reacted for 16 h. The system was concentrated to obtain a crude product, which was dissolved in dioxane (10 mL). A mixed solution of dioxane (5 mL) and ethanol (5 mL) was added dropwise at 0 ° C. After the addition was completed, the system was stirred at room temperature (20 ° C) for 1 h. The system was dissolved in ethyl acetate (20 mL), washed with a saturated potassium carbonate solution, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a yellow oil compound 1-2.

Step 2: Preparation of compound 1-3

Compound 1-2 (1.5 g, 6.32 mmol) was dissolved in methanol (15 mL). At 0°C, a methanol solution of sodium methoxide (1.25 g, 6.96 mmol, 30% by weight) was added dropwise. After the addition was completed, the system was stirred at 0°C for 15 min, then heated to room temperature (20°C) and stirred for 1 h. The system was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL), washed with saturated ammonium chloride solution, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude compound 1-3, which was directly used in the next step without further purification.

¹ H NMR (400MHz, CDCl ₃ ) 7.94 (d, 1H, J=12Hz), 4.09 (s, 3H), 3.93 (s, 3H).

Step 3: Preparation of compound 1-5

At room temperature (20°C), compound 1-3 (1.05 g, 4.79 mmol), 1-4 (0.776 g, 5.75 mmol), palladium acetate (107 mg, 0.479 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (275 mg, 0.479 mmol), cesium carbonate (3.142 g, 9.58 mmol) were dissolved in anhydrous dioxane (15 mL), and the system was heated to 100°C and stirred for 3 h under a nitrogen atmosphere. The system was cooled to room temperature, concentrated, diluted with water (100 mL), extracted with ethyl acetate (3x20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-10%) to obtain a white solid compound 1-5. MS (ESI) m/z (M+H) ⁺ = 319.2.

Step 4: Preparation of Compound 1-6

Compound 1-5 (200 mg, 0.629 mmol) and acetyl chloride (3 mL) were added to a 5 mL microwave tube, and the system was heated to 150°C for 3 h under microwave conditions. The system was cooled to room temperature and concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain a reddish brown oily compound 1-6.

MS (ESI) m/z (M+H) ⁺ = 361.2.

Step 5: Preparation of Compound 1-7

At room temperature (20°C), compound 1-6 (360 mg, 1 mmol) and potassium tert-butoxide (336 mg, 3 mmol) were dissolved in toluene (5 mL). Under a nitrogen atmosphere, the system was heated to 100°C and stirred for 3 h. After the system was cooled to room temperature, it was quenched with dilute hydrochloric acid (1N, 10 mL), extracted with ethyl acetate (2x10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain a yellow solid compound 1-7.

MS (ESI) m/z (M+H) ⁺ = 329.2.

Step 6: Preparation of Compound 1-8

Compound 1-7 (200 mg, 0.61 mmol) was dissolved in acetic acid (3 mL), and concentrated nitric acid (0.3 mL) was added dropwise at room temperature. After the addition was complete, the system was stirred at room temperature (20°C) for 30 min. The system was poured into ice water (100 mL), and a yellow solid was precipitated. The filter cake was dried under vacuum until the weight no longer decreased, and a yellow solid compound 1-8 was obtained.

MS (ESI) m/z (M+H) ⁺ = 374.2.

Step 7: Preparation of Compound 1-9

Compound 1-8 (200 mg, 0.54 mmol) was dissolved in acetic acid (2 mL), and hydrobromic acid (48%, 1 mL) was added at room temperature, and the system was heated to 100°C and stirred for 3 h. The reaction solution was concentrated to obtain crude compound 1-9, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 360.3.

Step 8: Preparation of Compound 1-10

Compound 1-9 (360 mg, 1 mmol) was added to N, N-diisopropylethylamine (2 mL). At room temperature, phosphorus oxychloride (1 mL) was added thereto. The reaction system turned black. The system was heated to 90 ° C and stirred for 1 h. The system was concentrated, the crude product was dissolved in ethyl acetate (10 mL), washed with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-10%) to obtain a yellow solid compound 1-10.

MS (ESI) m/z (M+H) ⁺ = 396.0.

Step 9: Preparation of Compound 1-12

Compound 1-10 (147 mg, 0.372 mmol), 1-11 (102 mg, 0.446 mmol), cuprous iodide (71.0 mg, 0.372 mmol), cesium carbonate (244 mg, 0.744 mmol) were dissolved in dioxane (4 mL), and the system was heated to 100 ° C and stirred for 2 h under a nitrogen atmosphere. The system was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain a yellow solid compound 1-12.

MS (ESI) m/z (M+H) ⁺ = 590.2.

Step 10: Preparation of Compound 1-14

Compound 1-12 (100 mg, 0.169 mmol), 1-13 (34.6 mg, 0.203 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (12.3 mg, 0.0169 mmol), potassium carbonate (46.6 mg, 0.338 mmol) were dissolved in a mixed solution of tetrahydrofuran (3 mL) and water (0.3 mL), and the system was heated to 80 ° C and stirred for 1 h under a nitrogen atmosphere. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 1-14.

MS (ESI) m/z (M+H) ⁺ = 680.2.

Step 11: Preparation of Compound 1-15

Compound 1-14 (30 mg, 0.044 mmol) was dissolved in N, N-dimethylacetamide (1 mL). At room temperature, a tetrahydrofuran solution of LiHMDS (24%, 0.1 mL) was added thereto. Under a nitrogen atmosphere, the system was heated to 160°C and stirred for 4 h. The system was cooled to room temperature, concentrated, and the residue was dissolved in ethyl acetate (3 mL), washed with water, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-40%) to obtain compound 1-15.

MS (ESI) m/z (M+H) ⁺ = 633.4.

Step 12: Preparation of compounds 1A and 1B

Compound 1-15 (8 mg, 0.0126 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added at room temperature and stirred at room temperature (20 ° C) for 1 h. The system was concentrated, and the residue was dissolved in dichloromethane (1 mL). The system was cooled to 0 ° C, and triethylamine (2.52 mg, 0.0252 mmol) and acryloyl chloride (2.27 mg, 0.0252 mmol) were added dropwise. After the addition was completed, the system was heated to room temperature (20 ° C) and reacted for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-performance preparative liquid chromatography (separation conditions: chromatographic column Welch Ultimate XB-C18 10*250mm, 5μm, aqueous phase 0.15TFA, organic phase acetonitrile, gradient 52%-70%, time 12min) to obtain compound 1A and compound 1B.

Compound 1A:

¹ H NMR (400MHz, MeOD-d4) 7.83 (d, 1H, J = 8Hz), 7.38-7.07 (m, 3H), 6.93-6.86 (m, 1H), 6.80-6.54 (m, 3H), 6.20 ( d,1H,J＝8Hz),5.75-5.67(m,2H),4.40-4.27(m,2H),4. 21-4.08(m,1H),4.02-3.82(m,3H),3.81-3.69(m,2H),3.58(d,3H),2.44-2.32(m,1H),1.08-0.98(m,3H ),0.92-0.85(m,3H),0.84-0.76(m,3H).MS(ESI)m/z(M+H) ⁺ =587.42.

Separation conditions: Column: Waters Xselect CSH C18 3.5μm, 100*4.6mm; Column temperature: 60℃; Mobile phase: Water (0.01% trifluoroacetic acid solution)-acetonitrile (0.01% trifluoroacetic acid solution); Acetonitrile: 5%-95% 7min, 95% 8min; Flow rate: 1.2mL/min. Retention time 6.175min

Compound 1B:

¹ H NMR (400MHz, MeOD-d4) 7.83 (d, 1H, J = 8Hz), 7.38-7.21 (m, 3H), 7.20-7.12 (m, 1H), 7.0-6.89 (m, 1H), 6.80- 6.57(m,3H),6.20-6.11(m,1H),5.73(d,1H,J＝8.0Hz),4. 38-4.21(m,4H),4.20-4.08(m,2H),4.07-3.93(m,2H),3.58(d,3H),2.35-2.25(m,1H),1.06-0.99(m,3H ),0.92-0.83(m,3H),0.82-0.79(m,3H).MS(ESI)m/z(M+H) ⁺ =587.4.

Separation conditions: chromatographic column: Waters Xselect CSH C18 3.5μm, 100*4.6mm; column temperature: 60℃; mobile phase: water (0.01% trifluoroacetic acid solution)-acetonitrile (0.01% trifluoroacetic acid solution); acetonitrile: 5%-95% 7min, 95% 8min; flow rate: 1.2mL/min. Retention time: 6.327min.

Example 2: Preparation of Compound 2

Step 1: Preparation of compound 2-2

Compound 2-1 (2.87 g, 15 mmol) was dissolved in anhydrous N, N-dimethylacetamide (10 mL). Sodium hydride (60%, 660 mg, 16.5 mol) was added in batches at 0°C. After addition, the system was heated to room temperature and stirred for 10 min. Chloromethyl methyl ether (2.4 g, 30 mmol) was added dropwise to the system. After addition, the system was stirred at room temperature for 10 min. The system was poured into ice water (50 mL) for quenching, and the system was extracted with methyl tert-butyl ether (3x50 mL). The organic phases were combined and washed once with a saturated sodium chloride aqueous solution. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-10%) to obtain a light yellow viscous compound 2-2.

¹ H NMR (400MHz, CDCl ₃ -d ₁ )7.24-7.18(m,1H),6.95-6.93(m,1H),6.83-6.79(m,1H),5.26(s,2H),3.52(s, 3H).

Step 2: Preparation of compound 2-3

Compound 1-2 (650 mg, 2.77 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). At -78 ° C, n-butyl lithium (2.5 N, 1.22 mL, 3.05 mmol) was added dropwise to the system. The system was stirred at -78 ° C for 30 min. Pinacol borate isopropyl ester (567 mg, 3.05 mmol) was then added dropwise to the system. The system was stirred at -78 ° C for 30 min. The system was warmed to room temperature, the reaction was quenched with water, extracted with ethyl acetate (10 mL), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure chromatography (ethyl acetate/petroleum ether (v/v) = 0-20%) to obtain a colorless oil 2-3.

Step 3: Preparation of compound 2-4

Compound 1-12 (50 mg, 0.0848 mmol), compound 2-3 (28.7 mg, 0.10 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (6.2 mg, 0.00848 mmol), potassium carbonate (23.4 mg, 0.169 mmol) were dissolved in a mixed solution of tetrahydrofuran (2 mL) and water (0.2 mL). Under a nitrogen atmosphere, the system was heated to 80 ° C and stirred for 2 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain a yellow solid compound 2-4.

MS (ESI) m/z (M+H) ⁺ = 710.2.

Step 4: Preparation of compound 2-5

Compound 2-4 (30 mg, 0.0423 mmol) was dissolved in N, N-dimethylacetamide (1 mL). Under nitrogen atmosphere, a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (24%, 0.1 mL) was added dropwise. The system was heated to 160°C for 4 h. The system was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain a light yellow solid compound 2-5.

MS (ESI) m/z (M+H) ⁺ = 663.2.

Step 5: Preparation of Compound 2-6

Compound 2-5 (6 mg, 0.009 mmol) and hydrochloric acid (6N, 0.5 mL) were added to a mixed solution of methanol (0.45 mL) and tetrahydrofuran (0.05 mL). The system was heated to 55°C and reacted for 15 min. The system was concentrated to obtain a crude product 2-6, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 519.2.

Step 6: Preparation of Product 2A and Product 2B

Compound 2-6 (5 mg, 0.0096 mmol) was dissolved in dichloromethane (1.0 mL), the system was cooled to 0°C, triethylamine (1.95 mg, 0.0193 mmol) and acryloyl chloride (1.73 mg, 0.0193 mmol) were added dropwise, and the system was reacted at 0°C for 1 h. The system was concentrated to obtain a crude product, which was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column Welch Ultimate XB-C1810*250mm, 5μm, aqueous phase 10mmol/L ammonium acetate, organic phase acetonitrile, gradient 38%-65%, time 15min) to obtain compounds 2A and 2B.

Compound 2A:

MS (ESI) m/z (M+H) ⁺ = 573.4.

Separation conditions: chromatographic column: Waters Xbridge C18 3.5μm, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; flow rate: 1.2mL/min. Retention time: 5.743min.

Compound 2B:

MS (ESI) m/z (M+H) ⁺ = 573.4.

Separation conditions: chromatographic column: Waters Xbridge C18 3.5μm, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; flow rate: 1.2mL/min. Retention time: 5.879min.

Example 3: Preparation of Compound 3

Step 1: Preparation of compound 3-2

The raw materials chloral hydrate (19.08g, 115.38mmol, 15.03mL) and sodium sulfate (122.92g, 865.37mmol) were dissolved in water (360mL), and the system was heated to 35°C. The aqueous solution (120mL) of the raw material 3-1 (20g, 96.15mmol), hydrochloric acid (12M, 10.82mL) and hydroxylamine hydrochloride (21.38g, 307.69mmol) were added thereto in sequence. After the addition, the system was heated to 90°C for 16h. A gray precipitate appeared in the system. The system was cooled to room temperature and filtered to obtain a filter cake. The filter cake was washed with water and then vacuum dried to obtain compound 3-2, which was directly used in the next step without further purification.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.34(s,1H),10.01(s,1H),7.78-7.74(m,1H),7.70(s,1H),7.31-7.26(m,1H ).

Step 2: Preparation of compound 3-3

Compound 3-2 (35 g, 125.43 mmol) was added to concentrated sulfuric acid (368.00 g, 3.75 mol, 200 mL) at 60 °C. After the addition, the system was heated to 90 °C and stirred for 3 h. The system was cooled to room temperature and poured into ice water to precipitate a black precipitate, which was filtered to obtain a filter cake, and the filter cake was dried to obtain a crude product A. The filtrate was extracted with ethyl acetate (500 mL x 2), the organic phases were combined, washed with saturated brine (500 mL), the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product B. The crude products A and B were combined to obtain compound 3-3, which was directly used in the next step without further purification.

Step 3: Preparation of compound 3-4

Compound 3-3 (29 g, 110.68 mmol) was dissolved in a sodium hydroxide aqueous solution (2M, 290.00 mL). Hydrogen peroxide (70.80 g, 624.44 mmol, 60 mL, purity 30%) was added dropwise at 0°C. After the addition was complete, the system was stirred at 0°C for 0.5 h, then heated to room temperature (20°C) and stirred for 16 h. The system was poured into ice water (300 mL), and the pH was adjusted to 6 with concentrated hydrochloric acid. A precipitate was precipitated in the system, and the filter cake was filtered. The filter cake was dried to obtain compound 3-4, which was directly used in the next step without further purification.

Step 4: Preparation of compound 3-5

Compound 3-4 (28 g, 111.11 mmol) was dissolved in methanol (300 mL), concentrated sulfuric acid (18.40 g, 187.60 mmol, 10 mL) was added thereto, and the system was heated to 75°C for 16 h under a nitrogen atmosphere. The system was concentrated, and the obtained crude product was extracted with ethyl acetate (200 mL) and water (300 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-20%) to obtain compound 3-5.

¹ H NMR (400MHz, CDCl ₃ ) δ7.46 (d, J = 8.6Hz, 1H), 5.73 (br s, 2H), 3.90 (br d, J = 2.0Hz, 3H)

Step 5: Preparation of Compound 3-6

Compound 3-5 (2.3 g, 8.65 mmol), compound 1-13 (2.20 g, 12.97 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (723 mg, 864.53 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (403 mg, 864.53 μmol) and potassium carbonate (3.58 g, 25.94 mmol) were dissolved in a mixed solution of dioxane (25 mL) and water (5 mL). Under a nitrogen atmosphere, the system was heated to 100 ° C and stirred for 16 hours. The system was concentrated and dissolved with ethyl acetate (50 mL), filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-20%) to obtain compound 3-6. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.48 (dd, J = 2.0, 9.9 Hz, 1H), 7.42-7.36 (m, 1H), 6.87-6.78 (m, 2H), 5.67 (br s, 2H), 3.92 (s, 3H), 3.82 (s, 3H).

Step 6: Preparation of Compound 3-7

Compound 3-6 (2 g, 6.43 mmol), cuprous iodide (1.24 g, 6.51 mmol), potassium iodide (2.16 g, 13.01 mmol) were dissolved in acetonitrile (30 mL), and tert-butyl nitrite (1.39 g, 13.45 mmol, 1.60 mL) was added thereto at 0°C. Under a nitrogen atmosphere, the system was heated to 80°C and stirred for 2 h. The system was filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-10%) to obtain compound 3-7.

¹ H NMR (400MHz, CDCl ₃ ) δ7.50 (dd, J = 1.5, 9.0Hz, 1H), 7.45-7.37 (m, 1H), 6.87-6.78 (m, 2H), 3.98 (s, 3H), 3.86-3.77(s,3H).

Step 7: Preparation of Compound 3-8

At room temperature (20°C), compound 3-7 (1.6 g, 3.79 mmol), compound 3-9 (640 mg, 4.26 mmol), tris(dibenzylideneacetone)dipalladium (350 mg, 382.21 μmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (221 mg, 381.94 μmol), cesium carbonate (3.7 g, 11.37 mmol) were dissolved in toluene (30 mL), and the system was heated to 110°C and stirred for 16 h under nitrogen atmosphere. The system was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-20%) to obtain compound 3-8.

¹ H NMR (400MHz, CDCl ₃ ) δ8.90 (d, J = 3.1 Hz, 1H), 8.29 (d, J = 4.9 Hz, 1H), 7.64 (dd, J = 1.9, 9.6 Hz, 1H), 7.39 -7.29(m,1H),6.94(t,J＝5.1Hz,1H),6.79-6.60(m,2H),3.97(s,3H),3.74(d,J＝15.7Hz,3H),3.55- 3.37(m,1H),2.20(s,3H),1.33-1.14(m,6H).MS(ESI)m/z(M+H) ⁺ =445.0.

Step 8: Preparation of compound 3-10

At room temperature (20°C), compound 3-8 (1.26 g, 2.83 mmol) was dissolved in N, N-dimethylformamide (15 mL), and sodium hydride (454 mg, 11.35 mmol, purity 60%) was added in batches. After the addition, acetyl chloride (888.59 mg, 11.32 mmol, 807.81 μL) was added dropwise. After the addition, the system was heated to 100°C under a nitrogen atmosphere for 8 hours. Saturated aqueous ammonium chloride solution (5 mL) was added to the system to quench the reaction, and 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain compound 3-10.

MS (ESI) m/z (M+H) ⁺ = 487.2.

Step 9: Preparation of compound 3-11

At room temperature (20°C), compound 3-10 (800 mg, 1.64 mmol) was dissolved in toluene (15 mL), and potassium tert-butoxide (1M, 5.33 mL) was added thereto. After the addition, the system was reacted at room temperature (20°C) for 0.5 h under a nitrogen atmosphere. Water (20 mL) was added to the system to quench the reaction, the pH was adjusted to neutral with 1N hydrochloric acid, and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 3-11, which was directly used in the next step without further purification.

¹ H NMR (400MHz, CDCl ₃ ) δ8.55 (t, J = 4.5Hz, 1H), 7.64 (br d, J = 8.6Hz, 1H), 7.39-7.27 (m, 1H), 7.19-7.06 (m ,1H),6.79-6.65(m,2H),6.41(s,1H),3.72(s,1.5H),3.66(s,1.5H),2.85-2.78(m,1H),2.08(d,J ＝5.7Hz,3H),1.31-1.07(m,6H).

MS (ESI) m/z (M+H) ⁺ = 455.1.

Step 10: Preparation of compound 3-12

Compound 3-11 (1 g, 2.20 mmol) was dissolved in glacial acetic acid (20 mL). Nitric acid (2.55 g, 40.40 mmol, 1.82 mL) was added dropwise to the system at room temperature (20 ° C). After the addition was completed, the system was heated to 80 ° C and stirred for 2 h. After the system was cooled to room temperature, most of the glacial acetic acid was removed by concentration, and the residue was poured into ice water (50 mL). The precipitate was precipitated and filtered. The filter cake was washed with water and dried to obtain compound 3-12, which was directly used in the next step without further purification.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.72 (d, J = 5.8 Hz, 1H), 7.97-7.74 (m, 2H), 7.48 (q, J = 8.1 Hz, 1H), 7.06-6.83 ( m,2H),3.74(s,1.5H),3.67(s,1.5H),3.18-3.05(m,1H),2.25(d,J＝7.5Hz,3H),1.30-1.09(m,6H) .

MS (ESI) m/z (M+H) ⁺ = 500.5.

Step 11: Preparation of compound 3-13

Compound 3-12 (900 mg, 1.80 mmol) and N,N-diisopropylethylamine (1.40 g, 10.81 mmol, 1.88 mL) were dissolved in acetonitrile (10 mL). Phosphorus oxychloride (828.92 mg, 5.41 mmol, 502.38 μL) was added thereto at room temperature. After the addition, the system was heated to 80°C and stirred for 2 h. The system was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 3-13.

¹ H NMR (400MHz, CDCl ₃ ) δ8.54 (t, J = 4.3Hz, 1H), 7.87-7.84 (m, 1H), 7.42-7.36 (m, 1H), 7.10 (t, J = 4.3Hz, 1H),6.85-6.67(m,2H),3.76(s,1.5H),3.70(s,1.5H),2.79-2.66(m,1H),2.13(s,1.5H),2.11(s,1.5 H),1.28-1.15(m,6H).

Step 12: Preparation of Compound 3-14

Compound 3-13 (700 mg, 1.35 mmol), 1-11 (467 mg, 2.03 mmol), N,N-diisopropylethylamine (873.44 mg, 6.76 mmol, 1.18 mL) were dissolved in acetonitrile (10 mL), and the system was heated to 80 ° C and stirred for 1 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-60%) to obtain compound 3-14.

¹ H NMR(400MHz,MeOD)δ8.57-8.36(m,1H),7.77(br d,J＝7.8Hz,1H),7.59-7.41(m,1H),7.33-7.21(m,1H), 7.07-6.89(m,1H),6.85-6.75(m,1H),4.45(br s,1H),4.02-3.91(m,2H),3.82-3.65(m,6H),3.16-3.29(m, 1H),2.96-2.72(m,1H),2.27-2.07(m,3H),1.60-1.36(m,12H),1.30-1.02(m,6H).MS(ESI)m/z(M+H ) ⁺ =712.3.

Step 13: Preparation of compound 3-15

Compound 3-14 (700 mg, 983.52 μmol) and Molecular sieves (1 g) were dissolved in N-methylpyrrolidone (10 mL), and a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1 M, 2.10 mL) was added thereto at room temperature. After the addition, the system was heated to 130°C and stirred for 24 h under a nitrogen atmosphere. The system was cooled to room temperature, water (50 mL) was added thereto, and extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-60%) to obtain compound 3-15.

¹ H NMR (400MHz, MeOD) δ8.42(d,J＝5.1Hz,1H),7.53(d,J＝9.7Hz,1H),7.46-7.34(m,1H),7.24(br d,J＝ 5.1Hz,1H),6.94-6.85(m,1H),6.79(t,J＝9.0Hz,1H),4.67-4.44(m,3H),4.50-4.35(m,1H),4.21-4.07(m ,1H),3.82-3.64(m,3H),3.57-3.39(m,2H),3.14-3.08(m,1H),2.75-2.61(m,1H),2.12-1.98(m,3H),1.64 (br d,J＝6.8Hz,3H),1.51(s,9H),1.23-1.04(m,6H).

MS (ESI) m/z (M+H) ⁺ = 665.3.

Step 14: Preparation of Compound 3-16

Compound 3-15 (180 mg, 270.79 μmol) was dissolved in anhydrous dichloromethane (3 mL). At 0°C, a dichloromethane solution of boron tribromide (339.20 mg, 1.35 mmol, 130.46 μL) was added thereto. After the addition, the system was heated to room temperature (20°C) and stirred for 2 h under a nitrogen atmosphere. Methanol (10 mL) was added to the system and stirred for 10 min. The system was concentrated and lyophilized to obtain compound 3-16 (hydrobromide), which was used directly in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 551.3.

Step 15: Preparation of compounds 3A, 3B, 3C, and 3D

Compound 3-16 (180 mg, 285.04 μmol, hydrobromide) was dissolved in tetrahydrofuran (5 mL) and saturated sodium bicarbonate aqueous solution (2.62 mL). Acrylic anhydride (43.59 mg, 345.68 μmol) was added thereto at room temperature (20°C). After the addition, the system was stirred at room temperature (20°C) for 2 h. Methanol (3 mL) and an aqueous solution of lithium hydroxide (21.80 mg, 910.16 μmol) were added to the system, and stirring was continued at room temperature (20°C) for 2 h. The system was adjusted to a neutral pH with 1N hydrochloric acid, extracted with ethyl acetate (10 mL x2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile%: 41%-51% 9.5min) to obtain compounds 3A and 3B.

Compound 3A

¹ H NMR (400MHz, MeOD) δ8.42 (d, J = 4.9 Hz, 1H), 7.54 (br d, J = 9.0 Hz, 1H), 7.31-7.16 (m, 2H), 6.86-6.79 (m, 1H),6.73-6.59(m,2H),6.27(dd,J＝2.0,16.8Hz,1H),5.81(d,J＝9.7Hz,1H),4.72-4.34(m,3H),4.32-4.09 (m,1H),3.82-3.41(m,3H),3.13(br s,1H),2.81-2.60(m,1H),2.20-1.99(m,3H),1.87-1.63(m,3H),1.17-1.04(m,6H).

MS (ESI) m/z (M+H) ⁺ = 605.3.

HPLC 98.77% purity; retention time 3.72 min.

Separation conditions: Chromatographic column: Ultimate C18 3.0*50mm, 3μm; Column temperature: 40°C; Mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 6min, 80% 2min; Flow rate: 1.2mL/min.

Compound 3B

¹ H NMR (400MHz, MeOD) δ8.42 (d, J = 5.1Hz, 1H), 7.54 (d, J = 7.9Hz, 1H), 7.33-7.14 (m, 2H), 6.83 (dd, J = 10.7 ,16.6Hz,1H),6.70-6.53(m,2H),6.27(dd,J＝2.0,16.8Hz,1H),5.82( d,J＝10.4Hz,1H),4.74-4.33(m,3H),4.31-4.04(m,1H),3.84-3.36(m,3H),3.15(brs,1H),2.87-2.56(m, 1H), 2.05 (d, J = 4.0Hz, 3H), 1.88-1.59 (m, 3H), 1.23-0.97 (m, 6H).

MS (ESI) m/z (M+H) ⁺ = 605.3.

HPLC 98.77% purity; retention time 3.59 min.

Separation conditions: Chromatographic column: Ultimate C18 3.0*50mm, 3μm; Column temperature: 40°C; Mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 6min, 80% 2min; Flow rate: 1.2mL/min.

Step 16: Separation of isomers of compound 3A

The diastereoisomer compound 3A was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALCEL OJ-H (250mm*30mm, 5μm); mobile phase: [0.1% ammonia solution-ethanol]; ethanol%: 30%-30%; flow rate: 60mL/min). After concentration, compound 3A-1 and compound 3A-2 were obtained.

Compound 3A-1

¹ H NMR (400MHz, MeOD) δ8.42 (d, J = 5.1Hz, 1H), 7.54 (d, J = 9.0Hz, 1H), 7.37-7.10 (m, 2H), 6.82 (dd, J = 10.7 ,16.6Hz,1H),6.68(d,J＝8.2Hz,1H),6.62(t,J＝8.8Hz,1H),6.27(dd,J＝1.8,16.8Hz,1H),5.81(d,J =1 0.4Hz,1H),4.68-4.54(m,2H),4.50-4.38(m,1H),4.31-4.05(m,1H),3.81-3.37(m,3H),3.17-3.08(m,1H) ,2.69-2.62(m,1H),2.05(s,3H),1.86-1.52(m,3H),1.15(d,J＝6.8Hz,3H),1.06(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 605.3.

HPLC 97.74% purity; retention time 3.606 min.

Separation conditions: Chromatographic column: Xbridge C18, 5μm, 2.1*50mm; Column temperature: 50°C; Mobile phase: water (0.02% ammonia solution)-acetonitrile; Acetonitrile: 10%-80% 6min, 80% 2min; Flow rate: 0.8mL/min.

SFC 100% ee. Retention time 3.864 min.

Compound 3A-2

¹ H NMR (400MHz, MeOD) δ8.42 (d, J＝4.9Hz, 1H), 7.54 (br d, J＝7.9Hz, 1H), 7.33-7.14 (m, 2H), 6.82 (dd, J＝ 10.6,16.8Hz,1H),6.71-6.56(m,2H),6.27(dd,J＝1.8,16.8Hz,1H),5.81(br d,J＝10.8Hz,1H),4.61(br s,2H ),4.53-4.09(m,2H),3.81-3.40(m,3H),3.14(br s,1H),2.80-2.66(m,1H),2.03(s,3H),1.80-1.66(m,3H),1.15-1.10(m,6H).

MS (ESI) m/z (M+H) ⁺ = 605.3.

HPLC 95.13% purity; retention time 3.674 min.

Separation conditions: Chromatographic column: Xbridge C18, 5μm, 2.1*50mm; Column temperature: 50°C; Mobile phase: water (0.02% ammonia solution)-acetonitrile; Acetonitrile: 10%-80% 6min, 80% 2min; Flow rate: 0.8mL/min.

SFC 98.88% ee. Retention time 4.332 min.

Step 17: Separation of isomers of compound 3B

The diastereoisomer compound 3B was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALCEL OJ-H (250mm*30mm, 5μm); mobile phase: [0.1% ammonia solution-ethanol]; ethanol%: 30%-30%; flow rate: 60mL/min). After concentration, compound 3B-1 and compound 3B-2 were obtained.

Compound 3B-1

¹ H NMR (400MHz, MeOD) δ8.42 (d, J＝5.1Hz, 1H), 7.54 (br d, J＝9.0Hz, 1H), 7.34-7.12 (m, 2H), 6.82 (dd, J＝ 10.7,16.6Hz,1H),6.75-6.51(m,2H),6.27(dd,J＝1.8,16.8Hz,1H),5.81(br d,J＝10.1Hz,1H),4.74-4.57(m, 2H),4.45(d,J＝10.1Hz,1H),4.31-4.09(m,1H),3.74(br d,J＝9.7Hz,1H),3.63-3.43(m,2H),3.15-3.08(m,1H),2.69-2.62(m,1H),2.05(s,3H),1.86-1.61(m, 3H), 1.13 (dd, J＝6.7, 13.1Hz, 6H).

MS (ESI) m/z (M+H) ⁺ = 605.3.

HPLC 95.70% purity; retention time 3.669 min.

Separation conditions: Chromatographic column: Xbridge C18, 5μm, 2.1*50mm; Column temperature: 50°C; Mobile phase: water (0.02% ammonia solution)-acetonitrile; Acetonitrile: 10%-80% 6min, 80% 2min; Flow rate: 0.8mL/min.

SFC 100% ee. Retention time 3.978 min.

Compound 3B-2

¹ H NMR (400MHz, MeOD) δ8.42 (d, J＝4.9Hz, 1H), 7.54 (br d, J＝8.8Hz, 1H), 7.31-7.14 (m, 2H), 6.82 (dd, J＝ 10.8,16.8Hz,1H),6.68(d,J＝8.4Hz,1H),6.62(t,J＝8.7Hz,1H),6.27(br dd,J＝1.8,16.8Hz,1H),5.81(br d,J＝10.6Hz,1H),4.65(br d,J＝13.2Hz,1H),4.56-4.34(m,2H),4.27-4.07(m,1H),3.83-3.43(m,3H), 3.15(br s,1H),2.76-2.63(m,1H),2.04(s,3H),1.86-1.59(m,3H),1.15(d,J＝6.6Hz,3H),1.07(d,J＝6.8Hz ,3H).

MS (ESI) m/z (M+H) ⁺ = 605.3.

HPLC 98.65% purity; retention time 3.581 min.

Separation conditions: Chromatographic column: Xbridge C18, 5μm, 2.1*50mm; Column temperature: 50°C; Mobile phase: water (0.02% ammonia solution)-acetonitrile; Acetonitrile: 10%-80% 6min, 80% 2min; Flow rate: 0.8mL/min.

SFC 100% ee. Retention time 4.607 min.

Example 4: Preparation of Compound 4

Step 1: Preparation of compound 4-2

The raw materials chloral hydrate (22g, 133.01mmol, 17.32mL) and sodium sulfate (168.20g, 1.18mol, 120.14mL) were dissolved in water (360mL), and the system was heated to 35°C. The aqueous solution (120mL) of the raw material 4-1 (25g, 131.57mmol), hydrochloric acid (12M, 14.80mL) and hydroxylamine hydrochloride (29.26g, 421.02mmol) were added thereto in sequence. After the addition, the system was heated to 90°C for 16h. A yellow precipitate appeared in the system. The system was cooled to room temperature and filtered to obtain a filter cake. The filter cake was washed with water and dissolved in ethyl acetate (300mL), filtered, and the filtrate was concentrated to obtain compound 4-2, which was directly used in the next step without further purification. MS (ESI) m/z (M+H) ⁺ = 262.9.

Step 2: Preparation of compound 4-3

At 60°C, compound 4-2 (30.8 g, 117.99 mmol) was added to concentrated sulfuric acid (460.00 g, 4.60 mol, 250 mL, purity 98%). After the addition, the system was heated to 90°C and stirred for 3 h. The system was cooled to room temperature and poured into ice water to precipitate a yellow precipitate, which was filtered to obtain a filter cake. The filter cake was dried to obtain a yellow solid 4-3, which was directly used in the next step without further purification.

Step 3: Preparation of compound 4-4

Compound 4-3 (22 g, 90.16 mmol) was dissolved in a sodium hydroxide aqueous solution (2M, 225.39 mL). Hydrogen peroxide (51.11 g, 450.79 mmol, 43.31 mL, purity 30%) was added dropwise at 0°C. After the addition was complete, the system was stirred at 0°C for 0.5 h, then heated to room temperature (20°C) and stirred for 16 h. The system was poured into ice water (400 mL), and the pH was adjusted to 6 with concentrated hydrochloric acid. A precipitate was precipitated in the system, and the filter cake was filtered. The filter cake was dried to obtain compound 3-4, which was directly used in the next step without further purification.

Step 4: Preparation of compound 4-5

Compound 4-4 (20.5 g, 87.60 mmol) was dissolved in N,N-dimethylformamide (100 mL), and N-chlorosuccinimide (11.70 g, 87.60 mmol) was added thereto at room temperature (20°C). After the addition, the system was heated to 70°C and stirred for 16 h under a nitrogen atmosphere. After the system was cooled to room temperature, ice water was poured into the system, and a precipitate was precipitated. The filter cake was filtered, and the filter cake was washed with water and dried to obtain compound 4-5, which was directly used in the next step without further purification.

Step 5: Preparation of Compound 4-6

Compound 4-5 (15 g, 55.87 mmol) was dissolved in methanol (100 mL), and thionyl chloride (67.50 g, 567.37 mmol 41.16 mL) was added dropwise thereto. The system was heated to 75°C and stirred for 16 h under a nitrogen atmosphere. The system was concentrated, and the obtained crude product was dissolved in ethyl acetate (200 mL). The organic phase was washed with saturated sodium bicarbonate aqueous solution (80 mL) and saturated brine (80 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-10%) to obtain compound 4-6.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.68 (d, J = 2.0Hz, 1H), 6.86 (s, 2H), 3.83 (s, 3H).

MS (ESI) m/z (M+H) ⁺ = 283.8.

Step 6: Preparation of Compound 4-8

Compound 4-6 (6 g, 21.24 mmol), compound 4-7 (10 g, 43.10 mmol), tris(dibenzylideneacetone)dipalladium (840 mg, 1.46 mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (2.03 g, 4.25 mmol), and potassium carbonate (7.34 g, 53.10 mmol) were dissolved in a mixed solution of dioxane (100 mL) and water (20 mL). Under a nitrogen atmosphere, the system was heated to 100 ° C and stirred for 16 h. After the system was concentrated, it was extracted with ethyl acetate (50 mL x 2) and water (80 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-10%) to obtain compound 4-8.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.83-7.77 (m, 1H), 7.67 (d, J = 1.7Hz, 1H), 7.03 (d, J = 8.5Hz, 1H), 6.96 (t, J＝8.7Hz,1H),6.73(s,2H),3.86(s,3H),3.77(s,3H).

MS (ESI) m/z (M+H) ⁺ = 328.0.

Step 7: Preparation of Compound 4-9

Compound 4-8 (4.8 g, 14.65 mmol) was dissolved in glacial acetic acid (50 mL), and acetic anhydride (4.49 g, 43.94 mmol, 4.12 mL) was added dropwise at 0°C, and the system was heated to room temperature (20°C) for 36 hours. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-100%) to obtain compound 4-9.

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.05 (s, 1H), 7.71 (s, 1H), 7.54 (q, J = 8.1Hz, 1H), 7.06 (d, J = 8.5Hz, 1H) ,6.99(t,J＝8.7Hz,1H),3.79(s,3H),3.77(s,3H),2.03(s,3H).

MS (ESI) m/z (M+H) ⁺ = 370.0.

Step 8: Preparation of Compound 4-10

Compound 4-9 (4 g, 10.82 mmol) and potassium carbonate (4.49 g, 32.45 mmol) were dissolved in N, N-dimethylformamide (40 mL), and iodomethane (4.61 g, 32.45 mmol, 2.02 mL) was added thereto. The system was stirred at room temperature (20°C) for 16 h. The system was filtered, the filtrate was poured into water (100 mL), extracted with ethyl acetate (100 mL x 2), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 4-10. MS (ESI) m/z (M+H) ⁺ = 384.0.

Step 9: Preparation of Compound 4-11

At room temperature (20°C), compound 4-10 (4.1 g, 10.68 mmol) was dissolved in toluene (60 mL), and potassium tert-butoxide (1 M, 21.37 mL) was added thereto. After the addition, the system was reacted at room temperature (20°C) for 4 h under a nitrogen atmosphere. 1 M hydrochloric acid was added to the system to quench the reaction, and after dilution with water (80 mL), it was extracted with ethyl acetate (80 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was slurried with methanol to obtain compound 4-11, which was directly used in the next step without further purification.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.88 (s, 1H), 7.84 (s, 1H), 7.54 (q, J = 7.8Hz, 1H), 7.10-6.95 (m, 2H), 5.98 ( s,1H),3.78(s,3H),3.65(d,J=9.3Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 351.9.

Step 10: Preparation of Compound 4-12

Compound 4-11 (1 g, 2.84 mmol) was dissolved in glacial acetic acid (20 mL). Nitric acid (2.80 g, 44.44 mmol, 2 mL) was added dropwise to the system at room temperature (20 ° C). After the addition was completed, the system was heated to 80 ° C and stirred for 1 h. After the system was cooled to room temperature, most of the glacial acetic acid was removed by concentration, and the residue was poured into ice water (25 mL), extracted with ethyl acetate (20 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 4-12, which was directly used in the next step without further purification.

¹ H NMR (400MHz, CDCl ₃ ) δ13.53 (br s, 1H), 8.21 (d, J = 1.8Hz, 1H), 7.47 (t, J = 6.8, 8.4Hz, 1H), 6.91-6.83 (m ,2H),3.87(d,J＝8.8Hz,3H),3.82(s,3H).

MS (ESI) m/z (M+H) ⁺ = 397.0.

Step 11: Preparation of Compound 4-13

Compound 4-12 (1.1 g, 2.77 mmol) and N,N-diisopropylethylamine (1.43 g, 11.09 mmol, 1.93 mL) were dissolved in acetonitrile (10 mL). Phosphorus oxychloride (1.32 g, 8.61 mmol, 800 μL) was added thereto at room temperature. After the addition, the system was heated to 80°C and stirred for 1 h. The system was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-10%) to obtain compound 4-13.

¹ H NMR (400MHz, CDCl ₃ ) δ8.07 (d, J＝1.8Hz, 1H), 7.48 (t, J＝6.8, 8.4Hz, 1H), 6.91-6.83 (m, 2H), 3.96 (d, J＝9.3Hz,3H),3.82(s,3H).

MS (ESI) m/z (M+H) ⁺ = 414.9.

Step 12: Preparation of Compound 4-14

Compound 4-13 (0.8 g, 1.93 mmol), 1-11 (621.28 mg, 2.70 mmol), N,N-diisopropylethylamine (747.10 mg, 5.78 mmol, 1.01 mL) were dissolved in acetonitrile (10 mL), and the system was heated to 80 ° C and stirred for 3 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain compound 4-14.

¹ H NMR (400MHz, MeOD) δ7.91 (s, 1H), 7.52 (dt, J = 6.8, 8.4Hz, 1H), 7.00 (d, J = 8.3Hz, 1H), 6.89 (t, J = 8.7 Hz,1H),4.38(br s,1H),4.16(br d,J＝13.8Hz,1H),3.88-3.74(m,8H),3.72-3.52(m,3H),2.98(br d,J ＝12.3Hz,1H),1.50(s,9H),1.34(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 609.1.

Step 13: Preparation of Compound 4-15

Compound 4-14 (0.86 g, 1.41 mmol) and Molecular sieves (0.5 g) were dissolved in N-methylpyrrolidone (10 mL). At room temperature, a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1 M, 2.82 mL) was added thereto. After the addition, the system was heated to 140°C and stirred for 5 h under a nitrogen atmosphere. The system was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (80 mL) and then washed with water (60 mL x 2) and saturated brine (60 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain a crude product, and the crude product was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile%: 60%-90% 9.5min) to obtain compound 4-15.

¹ H NMR (400MHz, MeOD) δ7.76 (s, 1H), 7.51-7.44 (m, 1H), 6.97 (d, J = 8.5Hz, 1H), 6.86 (t, J = 8.5Hz, 1H), 4.60(s,1H),4.51-4.39(m,2H),4.33(dd,J＝2.8,10.8Hz,1H),4.10(d,J＝14.8Hz,1H),3.92(br s,1H), 3.88(d,J＝9.0Hz,3H),3.80(s,3H),3.37(br d,J＝12.5Hz,1H),3.00(br d,J＝12.8Hz,1H),1.60(d,J =7.0Hz,3H),1.50(s,9H).

MS (ESI) m/z (M+H) ⁺ = 562.1.

Step 14: Preparation of Compound 4-16

Compound 4-15 (0.08 g, 142.35 μmol) was dissolved in anhydrous dichloromethane (1 mL). At 0°C, a dichloromethane solution of boron tribromide (260 mg, 1.04 mmol, 0.1 mL) was added. After the addition, the system was heated to room temperature (20°C) and stirred for 2 h under a nitrogen atmosphere. Methanol (2 mL) was added to the system and stirred for 10 min. After the system was concentrated, compound 4-16 (hydrobromide) was obtained and used directly in the next step without further purification.

Step 15: Preparation of compounds 4A and 4B

Compound 3-17 (0.1 g, 189.12 μmol, hydrobromide) was dissolved in tetrahydrofuran (5 mL) and saturated sodium bicarbonate aqueous solution (2.82 mL). Acrylic anhydride (0.02 g, 158.59 μmol) was added at room temperature (20 ° C). After the addition, the system was stirred at room temperature (20 ° C) for 2 h. Methanol (3 mL) and an aqueous solution of lithium hydroxide (31.74 mg, 756.47 μmol) were added to the system, and the stirring was continued at room temperature (20 ° C) for 2 h. The system was adjusted to a neutral pH with 1N hydrochloric acid, extracted with ethyl acetate (10 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile%: 43%-73% 9.5min) to obtain compounds 4A and 4B.

Compound 4A

¹ H NMR (400MHz, MeOD) δ7.78 (br s, 1H), 7.34-7.26 (m, 1H), 6.87-6.66 (m, 3H), 6.26 (dd, J = 1.8, 16.8Hz, 1H), 5.80(br d,J＝9.5Hz,1H),4.67-4.03(m,4H),3.89(d,J＝9.0Hz,3H),3.72(br s,1H),3.46(br d,J＝14.6 Hz,2H),3.03(br d,J=10.0Hz,1H),1.77-1.61(m,3H).

MS (ESI) m/z (M+H) ⁺ = 502.2.

HPLC 96.17% purity; retention time 9.28 min.

Separation conditions: Chromatographic column: YMC-Pack ODS-A150*4.6mm, 5μm; Column temperature: 40°C; Mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min.

Compound 4B

¹ H NMR (400MHz, MeOD) δ7.78 (br s, 1H), 7.35-7.25 (m, 1H), 6.86-6.67 (m, 3H), 6.26 (dd, J = 1.9, 16.7Hz, 1H), 5.81(br s,1H),4.69-4.04(m,4H),3.89(d,J＝9.0Hz,3H),3.70(br d,J＝15.3Hz,1H),3.47(br d,J＝11.8 Hz,2H),3.03(br s,1H),1.78-1.62(m,3H).MS(ESI)m/z(M+H) ⁺ =502.2.

HPLC 97.7% purity; retention time 9.60 min.

Separation conditions: Chromatographic column: YMC-Pack ODS-A150*4.6mm, 5μm; Column temperature: 40°C; Mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min.

Example 5: Preparation of Compound 5

Step 1: Preparation of compound 5-1

At room temperature (20°C), compound 1-3 (29.57 g, 135.0 mmol, 1.0 eq), 3-9 (20.25 g, 135.0 mmol, 1.0 eq), palladium acetate (3.038 g, 13.5 mmol, 0.1 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.817 g, 13.5 mmol, 0.1 eq), cesium carbonate (88.02 g, 270.0 mmol, 2.0 eq) were dissolved in anhydrous dioxane (270 mL), and the system was heated to 120°C and stirred for 3 h under a nitrogen atmosphere. The system was cooled to room temperature, quenched with saturated aqueous ammonium chloride solution (1 L), extracted with ethyl acetate (3 x 500 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-10%) to obtain compound 5-1.

MS (ESI) m/z (M+H) ⁺ = 334.1.

Step 2: Preparation of compound 5-2

Compound 5-1 (13.32 g, 40 mmol, 1.0 eq) was dissolved in N, N-dimethylformamide (150 mL). Sodium hydride (4.8 g, 120 mmol, 3.0 eq) was added in batches at room temperature (20 ° C). After the addition, the system was stirred at room temperature (20 ° C) for 10 min, and acetyl chloride (7.02 g, 120 mmol, 3.0 eq) was added dropwise. After the addition was completed, the system was heated to 100 ° C and stirred for 2 h. The system was cooled to room temperature, saturated aqueous ammonium chloride solution (50 mL) was added to quench the reaction, diluted with 1000 mL of water, extracted with ethyl acetate (3x500 mL), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by reverse phase medium pressure column chromatography (acetonitrile/water (v/v) = 30-45%) to obtain compound 5-2.

MS (ESI) m/z (M+H) ⁺ = 344.1.

Step 3: Preparation of compound 5-3

Compound 5-2 (688 mg, 2 mmol) was dissolved in acetic acid (10 mL), and concentrated nitric acid (2 mL) was added dropwise at room temperature. After the addition was complete, the system was heated to 50°C and stirred for 1 h. The system was cooled to room temperature and poured into ice water (100 mL), and the pH was adjusted to neutral with 10N sodium hydroxide, and extracted with ethyl acetate (4x100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 5-3, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 389.40.

Step 4: Preparation of compound 5-4

Compound 5-3 (300 mg, 0.77 mmol) was dissolved in acetic acid (3 mL), and hydrobromic acid (48%, 1.5 mL) was added at room temperature. After the addition, the system was heated to 100°C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated to obtain compound 5-4, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 375.00.

Step 5: Preparation of compound 5-5

Compound 5-4 (290 mg, 0.77 mmol) and N,N-diisopropylethylamine (0.77 mL, 4.64 mmol) were dissolved in acetonitrile (10 mL). Phosphorus oxychloride (0.44 mL) was added at room temperature, and the reaction system turned black. The system was heated to 80 ° C and stirred for 1 h. The system was concentrated, the crude product was dissolved in ethyl acetate (10 mL), washed with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-15%) to obtain compound 5-5.

MS (ESI) m/z (M+H) ⁺ = 411.00.

Step 6: Preparation of compound 5-6

Compound 5-5 (120 mg, 0.3 mmol), 1-11 (73 mg, 0.315 mmol), cuprous iodide (57.3 mg, 0.3 mmol), cesium carbonate (197 mg, 0.6 mmol) were dissolved in dioxane (4 mL), and the system was heated to 100 ° C and stirred for 2 h under a nitrogen atmosphere. The system was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-40%) to obtain compound 5-6.

MS (ESI) m/z (M+H) ⁺ = 605.20.

Step 7: Preparation of compound 5-7

Compound 5-6 (100 mg, 0.165 mmol), compound 2-13 (94 mg, 0.332 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (12.3 mg, 0.0169 mmol), potassium carbonate (46.6 mg, 0.338 mmol) were dissolved in a mixed solution of tetrahydrofuran (3 mL) and water (0.3 mL), and the system was heated to 80 ° C and stirred for 1 h under a nitrogen atmosphere. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-40%) to obtain compound 5-7.

MS (ESI) m/z (M+H) ⁺ = 725.40.

Step 8: Preparation of Compound 5-8

Compound 5-7 (25 mg, 0.034 mmol) was dissolved in N, N-dimethylacetamide (2 mL). At room temperature, a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (24%, 0.5 mL) was added thereto. Under a nitrogen atmosphere, the system was heated to 160°C and stirred for 10 h. The system was cooled to room temperature, concentrated, and the residue was dissolved in ethyl acetate (3 mL), washed with water, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-40%) to obtain compound 5-8.

MS (ESI) m/z (M+H) ⁺ = 678.40.

Step 9: Preparation of compound 5-9

Compound 5-8 (13 mg, 0.0192 mmol) and hydrochloric acid (6N, 1 mL) were added to a mixed solution of methanol (0.9 mL) and tetrahydrofuran (0.1 mL). The system was heated to 55°C and reacted for 15 min. The system was concentrated to obtain a crude compound 5-9, which was directly used in the next step without further purification.

MS(ESI) m/z(M+H) ⁺ =534.20.

Step 10: Preparation of compounds 5A and 5B

Compound 5-9 (12 mg, 0.0192 mmol) was dissolved in dichloromethane (1 mL), and triethylamine (2.52 mg, 0.0252 mmol) and acryloyl chloride (2.27 mg, 0.0252 mmol) were added dropwise at 0°C. After the addition was completed, the system was heated to room temperature (20°C) and reacted for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column WelchXtimate C18 10*250 mm, 5 μm; column temperature 25°C; mobile phase: water (10 mM/L ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile 32%-47% 16 min; flow rate 8 mL/min) to obtain compound 5A and compound 5B.

Compound 5A:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.00 (s, 1H), 8.36 (d, J = 4.9Hz, 1H), 7.79 (d, J = 8.9Hz, 1H), 7.24–

7.06(m,2H),6.87–6.71(m,1H),6.68–6.51(m,2H),6.10(d,J＝16.7Hz,1H),5.69(d,J＝10.5Hz,1H),4.51 –4.07(m,3H),3.67–3.42(m,4H),2.65–2.48(m,2H),1.73(s,3H),1.55–1.48(m,3H),0.98(d,J＝6.7Hz ,3H),0.84(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 588.20.

HPLC 100% purity; retention time 4.917 min.

Separation conditions: Chromatographic column: Waters Xbridge C18 3.5μm, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; flow rate: 1.2mL/min.

Compound 5B:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.38(brs,1H),8.44(d,J＝4.9Hz,1H),7.92(d,J＝8.5Hz,1H),7.37–7.18(m, 2H),6.97–6.80(m,1H),6.79–6.62(m,2H),6.21(dd,J＝16.7,2.1Hz,1H),5.82(d,J＝10 .6Hz,1H),4.51–4.07(m,3H),3.67–3.42(m,4H),2.65–2.48(m,1H),2.48–2.42(m,1H),1.91(s,3H),1.72 –1.53(m,3H),1.05(d,J＝6.7Hz,3H),0.90(d,J＝6.7Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 588.20.

HPLC 100% purity; retention time 4.975 min.

Separation conditions: Chromatographic column: Waters Xbridge C18 3.5μm, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; flow rate: 1.2mL/min.

Example 6: Preparation of Compound 6

Step 1: Preparation of compound 6-1

Compound 5-10 (90 mg, 0.15 mmol), compound 1-13 (51 mg, 0.30 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (11 mg, 0.015 mmol), potassium carbonate (41 mg, 0.3 mmol) were dissolved in a mixed solution of tetrahydrofuran (3 mL) and water (0.3 mL), and the system was heated to 80 ° C and stirred for 1 h under a nitrogen atmosphere. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-40%) to obtain compound 6-1.

MS (ESI) m/z (M+H) ⁺ = 695.40.

Step 2: Preparation of compound 6-2

Compound 6-1 (40 mg, 0.058 mmol) was dissolved in N, N-dimethylacetamide (2 mL). At room temperature, a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (24%, 0.5 mL) was added thereto. Under a nitrogen atmosphere, the system was heated to 160°C and stirred for 10 h. The system was cooled to room temperature, concentrated, and the residue was dissolved in ethyl acetate (3 mL), washed with water, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-40%) to obtain compound 6-2.

MS (ESI) m/z (M+H) ⁺ = 648.40.

Step 3: Preparation of compounds 6A and 6B

Compound 6-2 (14 mg, 0.022 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added at room temperature and stirred at room temperature (20 ° C) for 1 h. The system was concentrated, and the residue was dissolved in dichloromethane (2 mL). The system was cooled to 0 ° C, and triethylamine (0.014 mL, 0.1 mmol) and acryloyl chloride (4 mg, 0.04 mmol) were added dropwise. After the addition was completed, the system was heated to room temperature (20 ° C) and reacted for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid chromatography (separation conditions: chromatographic column Welch Xtimate C18 10*250mm, 5μm; column temperature 25°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile 28%-50% 19min; flow rate 8mL/min) to obtain compound 6A and compound 6B.

Compound 6A:

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.44–8.24(m,1H),7.80(d,J＝9.0Hz,1H),7.51–7.31(m,1H),7.15(dd,J＝4.9 ,0.8Hz,1H),6.97–6.64(m,3H),6.10(d,J＝16.6Hz,1H),5.70(d,J＝15.0Hz,1H),4.87–

4.09(m,2H),3.59(d,J＝3.5Hz,3H),3.55–3.45(m,5H),2.56–2.50(m,2H),1.72(d,J＝8.1Hz,3H),1.62 –1.39(m,3H),1.09–0.94(m,3H),0.92–0.72(m,3H).

MS (ESI) m/z (M+H) ⁺ = 602.20.

HPLC 100% purity; retention time 5.388 min.

Separation conditions: Chromatographic column: Waters Xbridge C18 3.5μm, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; flow rate: 1.2mL/min.

Compound 6B:

¹ H NMR (400MHz, Chloroform-d) δ8.67 (s, 1H), 7.81 (d, J = 8.4Hz, 1H), 7.35 (q, J = 7.9Hz, 1H), 7.27–7.14 (m, 1H ),6.72(d,J＝8.5Hz,2H),6.66–6.50(m,1H),6.40(d,J＝16.4Hz,1H),5 .83(d,J＝10.3Hz,1H),4.52–4.27(m,2H),3.78–3.58(m,5H),3.58–3.37(m,2H),3.10(d,J＝12.6Hz,1H ),2.82–2.59(m,1H),2.13–1.98(m,1H),1.74(s,3H),1.31–0.96(m,9H).

MS (ESI) m/z (M+H) ⁺ = 602.20.

HPLC 100% purity; retention time 5.455 min.

Separation conditions: Chromatographic column: Waters Xbridge C18 3.5μm, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; flow rate: 1.2mL/min.

Example 7: Preparation of Compound 7

Step 1: Preparation of compound 7-2

Compound 1-10 (2000 mg, 5.063 mmol), 7-1 (2000 mg, 7.751 mmol), cuprous iodide (470.0 mg, 2.46 mmol), cesium carbonate (3280 mg, 10 mmol) were dissolved in dioxane (30 mL), and the system was heated to 100 ° C and stirred for 1 h under a nitrogen atmosphere. The system was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain compound 7-2.

MS (ESI) m/z (M+H) ⁺ = 618.2.

Step 2: Preparation of compound 7-3

Compound 7-2 (320 mg, 0.517 mmol) and iron powder (115 mg, 2.068 mmol) were dissolved in acetic acid (10 mL). Under nitrogen atmosphere, the system was heated to 80 °C and stirred for 1 h. The system was filtered through celite and the filtrate was concentrated to obtain crude compound 7-3. It was used directly in the next reaction without further purification.

MS (ESI) m/z (M+H) ⁺ = 556.2.

Step 3: Preparation of compound 7-4

Dissolve compound 7-3 (287 mg, 0.517 mmol) and potassium carbonate (276 mg, 2 mmol) in acetone (20 mL). Add iodomethane (284 mg, 2 mmol) at room temperature (20 ° C). After the addition, heat the system to 45 ° C and stir for 3 h under nitrogen atmosphere. Cool the system to room temperature and concentrate to obtain a crude product. The crude product is purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain compound 7-4.

MS (ESI) m/z (M+H) ⁺ = 570.2.

Step 4: Preparation of compound 7-5

Compound 7-4 (120 mg, 0.210 mmol), compound 2-3 (177 mg, 0.627 mmol), tetrakis(triphenylphosphine)palladium (240 mg, 0.207 mmol), sodium carbonate (90 mg, 0.849 mmol) were dissolved in a mixed solution of dioxane (5 mL) and water (0.5 mL). Under a nitrogen atmosphere, the system was heated to 100 ° C and stirred for 1 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 7-5.

MS (ESI) m/z (M+H) ⁺ = 690.3.

Step 5: Preparation of compound 7-6

Compound 7-5 (180 mg, 0.261 mmol) and hydrochloric acid (6N, 2 mL) were added to a mixed solution of methanol (10 mL) and tetrahydrofuran (1 mL). The system was heated to 55°C for 1 h. The system was concentrated to obtain a crude compound 7-6, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 546.2.

Step 6: Preparation of compound 7

Compound 7-6 (140 mg, 0.256 mmol) was dissolved in dichloromethane (5 mL), the system was cooled to 0°C, triethylamine (78 mg, 0.771 mmol) and acryloyl chloride (46 mg, 0.514 mmol) were added dropwise, and the system was reacted at 0°C for 0.5 h. The system was extracted with water (5 mL) and dichloromethane (3 mL), and the organic phase was concentrated to obtain a crude product. The crude product was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (10 mL), and lithium hydroxide (40 mg) was added thereto. After the addition was completed, the system was stirred at room temperature (20°C) for 30 min. The system was extracted with ethyl acetate (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30mm*3μm, mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile 51%-81% 9.5min; flow rate 30mL/min) to obtain compound 7.

Step 7: Preparation of compounds 7A and 7B

The diastereoisomer compound 7 was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% ammonia solution-ethanol]; ethanol%: 40%-40%; flow rate: 70 mL/min). After concentration, compound 7A and compound 7B were obtained.

Compound 7A

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.20–7.90(m,1H),7.54–7.41(m,2H),7.34(t,J＝7.4Hz,1H),7.20(p,J＝8.1 Hz,1H),7.16–7.07(m,1H),6.71–6.48(m,2H),6.24(d,J＝17.1Hz,1H),5.82(d,J＝11.1Hz,1H),4.75 (d,J＝14.3Hz,1H),4.65–4.46(m,1H),4.01–3.82(m,2H),3.48(s,3H),3.00–2.84(m,1H),2.45–2.32(m ,1H),1.67(d,J＝6.8Hz,3H),1.12(d,J＝6.8Hz,3H),0.96(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 600.0.

HPLC 100% purity; retention time 5.05 min.

Separation conditions: Chromatographic column: Ultimate C18 3.0*50mm, 3μm; Column temperature: 40°C; Mobile phase: water (0.0688% trifluoroacetic acid aqueous solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 6min, 80% 2min; Flow rate: 1.2mL/min.

SFC 100% ee. Retention time 3.939 min.

Separation conditions: Chromatographic column: Chiralcel OD-3 3μm, 100*4.6mm; column temperature: 35°C; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% 4min, 40% 2.5min, 5% 1.5min; flow rate: 2.8mL/min.

Compound 7B

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.06 (d, J = 8.9 Hz, 1H), 7.58–7.40 (m, 2H), 7.36–7.26 (m, 1H), 7.25–7.16 (m, 1H ),7.11(dd,J＝16.9,10.7Hz,1H),7.06–6.95(m,1H),6.67–6.44(m,2H),6.22(dd,J＝

16.9,1.9Hz,1H),5.80(dd,J＝10.7,2.0Hz,1H),4.74(d,J＝13.9Hz,1H),4.67–4.52(m,1H),3.99–

3.81(m,2H),3.45(s,3H),2.93(dd,J＝12.4,3.8Hz,1H),2.68(p,J＝7.0Hz,1H),1.65(d,J＝6.9Hz,3H ),1.17(d,J＝6.9Hz,3H),1.05(d,J＝6.9Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 600.0.

HPLC 100% purity; retention time 5.00 min.

Separation conditions: Chromatographic column: Ultimate C18 3.0*50mm, 3μm; Column temperature: 40°C; Mobile phase: water (0.0688% trifluoroacetic acid aqueous solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 6min, 80% 2min; Flow rate: 1.2mL/min.

SFC 100％ee. Retention time 4.329min

Separation conditions: Chromatographic column: Chiralcel OD-3 3μm, 100*4.6mm; column temperature: 35°C; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% 4min, 40% 2.5min, 5% 1.5min; flow rate: 2.8mL/min.

Example 8: Preparation of Compound 8

Step 1: Preparation of compound 8-2

The raw material 8-1 (10 g, 52.351 mmol) was dissolved in thionyl chloride (30 mL), and the system was heated to 85°C for 16 h. The system was concentrated, and the residue was dissolved in 1,4-dioxane (30 mL). The solution was slowly added to the stirred methanol at 0°C, and the system was heated to 70°C for 2 h. The system was concentrated to obtain compound 8-2.

Step 2: Preparation of compound 8-3

Compound 8-2 (4 g, 19.4 mmol) was dissolved in methanol (50 mL), and a methanol solution of sodium methoxide (4 mL, 21.3 mmol) was added dropwise thereto, and the system was reacted at room temperature (20°C) for 3 h. The system was concentrated, poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product 8-3.

MS (ESI) m/z (M+H) ⁺ = 202.0.

Step 3: Preparation of compound 8-4

At room temperature (20°C), compound 8-3 (1.48 g, 7.36 mmol), compound 3-9 (1.11 g, 7.36 mmol), palladium acetate (165 mg, 0.736 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (425 mg, 0.735 mmol), cesium carbonate (4.8 g, 14.73 mmol) were dissolved in dioxane (15 mL), and the system was heated to 110°C and stirred for 4 h under a nitrogen atmosphere. The system was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-20%) to obtain compound 8-4.

MS (ESI) m/z (M+H) ⁺ = 316.0.

Step 4: Preparation of compound 8-5

Compound 8-4 (1.58 g, 4.80 mmol) was dissolved in N,N-dimethylformamide (15 mL), N-chlorosuccinimide (0.706 g, 5.28 mmol) was added thereto, and the system was heated to 80°C for 5 h. The system was cooled to room temperature, poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-5%) to obtain compound 8-5.

MS (ESI) m/z (M+H) ⁺ = 350.0

Step 5: Preparation of compound 8-6

At room temperature (20°C), compound 8-5 (6.3 g, 7.82 mmol) was dissolved in N,N-dimethylformamide (30 mL). At 0°C, sodium hydride (2.17 g, 54.15 mmol) was added in batches. After the addition, the system was reacted at 0°C for 30 min, and acetyl chloride (3.85 mL, 54.15 mmol) was added dropwise. Water (30 mL) and a saturated aqueous solution of potassium carbonate were added to the system in sequence, and the system was reacted at room temperature (20°C) for 3 h. After extraction with EA (100 mL x 2), the aqueous phase was adjusted to pH 4-5 with hydrochloric acid (4N), and then extracted with ethyl acetate (100 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (methanol/dichloromethane (v/v) = 0-5%) to obtain compound 8-6.

MS (ESI) m/z (M+H) ⁺ = 360.0.

Step 6: Preparation of compound 8-7

Dissolve compound 8-6 (1.86 g, 5.18 mmol) in glacial acetic acid (30 mL), and add nitric acid (15 mL) dropwise to the system at room temperature (20°C). After the addition is complete, stir the system at room temperature (20°C) for 2 h. Concentrate the system to remove most of the glacial acetic acid, pour the residue into ice water (25 mL), adjust the pH to 5-6, filter, wash the filter cake with water and dry it to obtain compound 8-7.

MS (ESI) m/z (M+H) ⁺ = 405.0.

Step 7: Preparation of compound 8-8

Compound 8-7 (1 g, 2.47 mmol) was dissolved in a mixed solution of acetic acid (6 mL) and hydrobromic acid (8 mL). The system was heated to 100°C and reacted for 16 h. The system was spin-dried to obtain compound 8-8.

MS (ESI) m/z (M+H) ⁺ = 391.0.

Step 8: Preparation of Compound 8-9

Dissolve compound 8-8 (2.0 g, 5.13 mmol) and N,N-diisopropylethylamine (5 mL, 30.7 mmol) in acetonitrile (6 mL). Add phosphorus oxychloride (7 mL, 77 mmol) at room temperature (20 ° C). After the addition, heat the system to 80 ° C and stir for 2 h. Concentrate the system to obtain a crude product. The crude product is purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 8-9.

MS (ESI) m/z (M+H) ⁺ = 427.0.

Step 9: Preparation of Compounds 8-10

Compound 8-9 (754 mg, 1.77 mmol), 1-11 (447 mg, 1.955 mmol), cesium carbonate (1.15 g, 3.54 mmol), cuprous iodide (67 mg, 0.354 mmol) were dissolved in dioxane (5 mL). Under a nitrogen atmosphere, the system was heated to 100 ° C and stirred for 3 h. The system was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain compound 8-10.

Step 10: Preparation of Compounds 8-11

Compound 8-10 (345 mg, 0.556 mmol), compound 2-3 (470 mg, 1.669 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (23.4 mg, 0.032 mmol), potassium carbonate (44 mg, 0.321 mmol) were dissolved in a mixed solution of dioxane (4 mL) and water (1 mL). Under a nitrogen atmosphere, the system was heated to 100 ° C and stirred for 6 h. The system was concentrated, and the residue was dissolved in ethyl acetate (20 mL), washed with water, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-70%) to obtain compound 8-11.

MS (ESI) m/z (M+H) ⁺ = 741.2.

Step 11: Preparation of Compounds 8-12

Compound 8-11 (230 mg, 0.311 mmol) was dissolved in anhydrous 1,2-dichloroethane (10 mL). Triphenylphosphine (244 mg, 0.932 mmol), imidazole (42 mg, 0.622 mmol) and carbon tetrachloride (143 mg, 0.932 mmol) were added thereto at room temperature (20°C). After the addition, the system was heated to 80°C and stirred for 2 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 8-12.

Step 12: Preparation of Compounds 8-13

Compound 8-12 (150 mg, 0.198 mmol) was dissolved in glacial acetic acid (4 mL), iron powder (112 mg, 1.98 mmol) was added thereto, and the system was reacted at room temperature (20°C) for 1 h. The system was concentrated, and the residue was dissolved in ethyl acetate. The organic phase was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 8-13.

Step 13: Preparation of Compounds 8-14

Compound 8-13 (90 mg, 0.124 mmol) and N,N-diisopropylethylamine (48 mg, 0.371 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the system was heated to 120°C for 4 h. The system was cooled to room temperature, water (20 mL) was added thereto, and extracted with EA (15 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 8-14.

Step 14: Preparation of Compounds 8-15

Compound 8-14 (40 mg, 0.0578 mmol) was dissolved in tetrahydrofuran (2 mL), and sodium hydride (5 mg, 0.1156 mmol) was added thereto at 0°C. After the addition, the system was heated to room temperature and stirred for 30 min. Iodomethane (12.3 mg, 0.086 mmol) was added to the system, and after the addition, the system was stirred at room temperature (20°C) for 2 h. Water (5 mL) was added to the system to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL x 4). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 8-15.

Step 15: Preparation of Compound 8-16

Compound 8-15 (16 mg, 0.02266 mmol) and hydrochloric acid (6N, 1 mL) were added to a mixed solution of methanol (0.9 mL) and tetrahydrofuran (0.1 mL). The system was heated to 55°C and reacted for 15 min. The system was concentrated to obtain a crude product 8-16.

Step 16: Preparation of Compound 8

Compound 8-16 (13 mg) was dissolved in dichloromethane (2 mL), and triethylamine (11 mg, 0.112 mmol) and acryloyl chloride (7 mg, 0.084 mmol) were added thereto at room temperature (20 ° C). After the addition, the system was stirred at room temperature (20 ° C) for 2 h. Tetrahydrofuran (4 mL) and water (1 mL) and an aqueous solution of lithium hydroxide (31.74 mg, 756.47 μmol) were added to the system, and stirring was continued at room temperature (20 ° C) for 2 h. The system was adjusted to a neutral pH with 1N hydrochloric acid, extracted with ethyl acetate (10 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid chromatography (separation conditions: chromatographic column: Agilent 10 Prep-C8 250×21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 30%-50% in 16 min; flow rate 30 mL/min) to obtain compound 8.

Compound 8

¹ H NMR(400MHz, CDCl3)δ ¹ H NMR(400MHz, CDCl ₃ )8.56(s,1H),8.08(s,1H),7.15(s,1H),6.57(s,3H),6.34(s, 1H),5.73(s,1H),5.06(s,1H),4.67(s,0.5H),4.30(s,0.5H),3.53(s,2H),3.37–2.84(m,7H),2.67 (s,1H),1.93(s,3H),1.19(s,6H),1.05(s,3H).

MS (ESI) m/z (M+H) ⁺ = 617.3.

HPLC 99% purity; retention time 5.46 min.

Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; Mobile phase: [water (10 Mm ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% 7 min; Flow rate: 1.2 mL/min.

Example 9: Preparation of Compound 9

Step 1: Preparation of compound 9-1

Compound 8-3 (6 g, 29.8 mmol) and ethanol solution of methylamine (15 mL) were dissolved in ethanol (30 mL), and acetyl chloride (2.5 g, 2.36 mL, 31 mmol) was added dropwise. After the addition was complete, the system was heated to 100°C and reacted for 2 h. The system was concentrated, and the residue was dissolved in ethyl acetate (200 mL), washed with saturated brine (80 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-20%) to obtain compound 9-1.

Step 2: Preparation of compound 9-2

Compound 9-1 (2.02 g, 10.3 mmol) was dissolved in N,N-dimethylformamide (10 mL), N-chlorosuccinimide (1.5 g, 11.3 mmol) was added thereto, and the system was heated to 80°C for 2 h. The system was cooled to room temperature, poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-5%) to obtain compound 9-2.

MS (ESI) m/z (M+H) ⁺ = 231.0.

Step 3: Preparation of compound 9-3

Compound 9-2 (1.8 g, 7.82 mmol) and triethylamine (4.8 g, 6.6 mL, 47 mmol) were dissolved in dichloromethane (30 mL), and acetyl chloride (2.5 g, 2.36 mL, 31 mmol) was added dropwise. After the addition was completed, the system was heated to 50 °C for 16 h. The system was concentrated, and the residue was dissolved in ethyl acetate (100 mL). After washing with saturated brine (80 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-10%) to obtain compound 9-3. MS (ESI) m/z (M+H) ⁺ = 273.2.

Step 4: Preparation of compound 9-4

At room temperature (20°C), compound 9-3 (1.3 g, 1.91 mmol) was dissolved in toluene (20 mL), and potassium tert-butoxide (1.28 g, 11.46 mmol) was added thereto. After the addition, the system was reacted at room temperature (20°C) for 4 h under a nitrogen atmosphere. 1M hydrochloric acid was added to the system to quench the reaction, and after dilution with water (40 mL), it was extracted with ethyl acetate (50 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was slurried with methanol to obtain compound 9-4.

MS (ESI) m/z (M+H) ⁺ = 241.0.

Step 5: Preparation of compound 9-5

Compound 9-4 (1 g, 2.84 mmol) was dissolved in glacial acetic acid (20 mL). Nitric acid (2.80 g, 44.44 mmol, 2 mL) was added dropwise to the system at room temperature (20 ° C). After the addition was completed, the system was heated to 80 ° C and stirred for 1 h. After the system was cooled to room temperature, most of the glacial acetic acid was removed by concentration, and the residue was poured into ice water (25 mL), extracted with ethyl acetate (20 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 9-5.

MS (ESI) m/z (M+H) ⁺ = 286.0.

Step 6: Preparation of compound 9-6

Compound 9-5 (320 mg, 1.12 mmol) was dissolved in a mixed solution of glacial acetic acid (10 mL) and hydrobromic acid (5 mL), and the system was heated to 100° C. for 8 h. The system was spin-dried to obtain compound 9-6.

MS (ESI) m/z (M+H) ⁺ = 272.0.

Step 7: Preparation of compound 9-7

Dissolve compound 9-6 (300 g, 1.05 mmol) and N,N-diisopropylethylamine (781 mg, 6.06 mmol) in acetonitrile (2 mL). Add phosphorus oxychloride (2.46 g, 16.12 mmol) at room temperature. After the addition, heat the system to 80 ° C and stir for 1 h. Cool the system to room temperature and concentrate to obtain a crude product. The crude product is purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-20%) to obtain 150 mg of yellow solid compound 9-7.

MS (ESI) m/z (M+H) ⁺ = 308.3.

Step 8: Preparation of compound 9-8

Compound 9-7 (130 mg, 0.423 mmol), 1-11 (107 mg, 0.465 mmol), cesium carbonate (275 mg, 0.846 mmol) and cuprous iodide (16 mg, 0.0846 mmol) were dissolved in 1,4-dioxane (3 mL). Under a nitrogen atmosphere, the system was heated to 100 ° C and stirred for 3 h. The system was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain compound 9-8. MS (ESI) m/z (M+H) ⁺ = 502.2.

Step 9: Preparation of compound 9-9

Compound 9-8 (80 mg, 0.16 mmol), compound 2-3 (58.5 mg, 0.207 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (23.4 mg, 0.032 mmol), potassium carbonate (44 mg, 0.321 mmol) were dissolved in a mixed solution of dioxane (4 mL) and water (1 mL). Under a nitrogen atmosphere, the system was heated to 100 ° C and reacted for 6 hours. After the system was concentrated, it was extracted with ethyl acetate (20 mL x 2) and water (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-70%) to obtain compound 9-9.

MS (ESI) m/z (M+H) ⁺ = 622.2.

Step 10: Preparation of Compound 9-10

Compound 9-9 (86 mg, 0.138 mmol) was dissolved in N, N-dimethylacetamide (3 mL), and a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1 M, 0.8 mL) was added thereto at room temperature. After the addition, the system was heated to 160°C and stirred for 5 h under a nitrogen atmosphere. The system was cooled to room temperature and filtered, and the filtrate was diluted with ethyl acetate (20 mL), and then washed with water (10 mL x 2) and saturated brine (10 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-40%) to obtain compound 9-10.

MS (ESI) m/z (M+H) ⁺ = 575.2.

Step 11: Preparation of Compound 9-11

Compound 9-10 (32 mg, 0.0577 mmol) and hydrochloric acid (6N, 1 mL) were added to a mixed solution of methanol (0.9 mL) and tetrahydrofuran (0.1 mL). The system was heated to 55°C and reacted for 15 min. The system was concentrated to obtain a crude product 9-11.

Step 12: Preparation of compound 9

Compound 9-11 (24 mg, 0.056 mmol) was dissolved in dichloromethane (2 mL), and triethylamine (11 mg, 0.112 mmol) and acryloyl chloride (7 mg, 0.084 mmol) were added thereto at room temperature (20 ° C). After the addition, the system was stirred at room temperature (20 ° C) for 2 h. Tetrahydrofuran (4 mL) and water (1 mL) and an aqueous solution of lithium hydroxide (31.74 mg, 756.47 μmol) were added to the system, and stirring was continued at room temperature (20 ° C) for 2 h. The system was adjusted to a neutral pH with 1N hydrochloric acid, extracted with ethyl acetate (10 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid chromatography (separation conditions: chromatographic column: Agilent 10 Prep-C8 250×21.2 mm; mobile phase: [water (0.1% FA)-acetonitrile]; acetonitrile%: 30%-50% 9 min, flow rate 30 mL/min) to obtain compound 9.

Compound 9

¹ H NMR (400MHz, CDCl3) δ ¹ H NMR (400MHz, CDCl ₃ ) δ8.11 (s, 1H), 7.35 (td, J = 8.3, 6.5Hz, 1H), 6.90 (d, J = 8.3Hz, 1H),6.78(t,J＝9.1Hz,1H),6.57(s,1H),6.38(d,J＝17.0Hz,1H),5.80(d,J＝11.3Hz,1H),4.39(s, 2H),3.82(s,3H),3.64(s,1H),3.38(d,J＝13.4Hz,2H),2.99(d,J＝13.0Hz,1H),1.72(s,3H).MS( ESI)m/z(M+H) ⁺ =485.2.

HPLC 99% purity; retention time 5.27 min.

Separation conditions: Chromatographic column: Waters XSelect CSH C18, 4.6*100 mm, 3.5 μm; Mobile phase: [water (0.01% trifluoroacetic acid)-acetonitrile (0.01% trifluoroacetic acid)]; Acetonitrile: 5%-95% 7 min; Flow rate: 1.2 mL/min.

Example 10: Preparation of Compound 10

Step 1: Preparation of compound 10-1

Compound 1-12 (470 mg, 0.798 mmol) and triphenylphosphine (630 mg, 2.4 mmol) were added to 1,2-dichloroethane (20 mL), and carbon tetrachloride (370 mg, 2.4 mmol) was added thereto under a nitrogen atmosphere. After the addition, the system was heated to 80°C for 1 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain compound 10-1.

MS (ESI) m/z (M+H) ⁺ = 608.2.

Step 2: Preparation of compound 10-2

Compound 10-1 (330 mg, 0.54 mmol) was dissolved in glacial acetic acid (10 mL), iron powder (300 mg, 5.4 mmol) was added thereto, and the system was heated to 80°C for 1 h. The system was concentrated, and the residue was dissolved in ethyl acetate and filtered through diatomaceous earth. The filtrate after filtration was concentrated under vacuum and purified by column chromatography (ethyl acetate/petroleum ether (v/v) = 0-40%) to obtain compound 10-2.

MS (ESI) m/z (M+H) ⁺ = 578.2

Step 3: Preparation of compound 10-3

Compound 10-2 (200 mg, 0.347 mmol) and N,N-diisopropylethylamine (400 mg, 3.47 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the system was heated to 150°C for 3 h. The system was cooled to room temperature, water (20 mL) was added thereto, and extracted with EA (15 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain compound 10-3.

MS (ESI) m/z (M+H) ⁺ = 542.2.

Step 4: Preparation of compound 10-4

Compound 10-3 (130 mg, 0.24 mmol), compound 2-3 (135 mg, 0.48 mmol), tetrakis(triphenylphosphine)palladium (138 mg, 0.12 mmol), sodium carbonate (234 mg, 0.72 mmol) were dissolved in a mixed solution of dioxane (5 mL) and water (0.5 mL), and the system was heated to 100 ° C and stirred for 1 h under a nitrogen atmosphere. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-40%) to obtain compound 10-4.

MS (ESI) m/z (M+H) ⁺ = 662.2.

Step 5: Preparation of compound 10-5

Compound 10-4 (40 mg, 0.06 mmol) was dissolved in tetrahydrofuran (2 mL), and sodium hydride (7.2 mg, 0.18 mmol) was added thereto at 0°C. After the addition, the system was heated to room temperature and stirred for 30 min. Iodomethane (17 mg, 0.12 mmol) was added to the system, and after the addition, the system was stirred at room temperature (20°C) for 1 h. Water (5 mL) was added to the system to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL x 4). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain compound 10-5.

MS (ESI) m/z (M+H) ⁺ = 676.2.

Step 6: Preparation of compound 10-6

Compound 10-5 (30 mg, 0.044 mmol) and hydrochloric acid (6N, 2 mL) were added to a mixed solution of methanol (10 mL) and tetrahydrofuran (1 mL). The system was heated to 55°C and reacted for 15 min. The system was concentrated to obtain a crude product 10-6.

MS (ESI) m/z (M+H) ⁺ = 532.4.

Step 7: Preparation of compound 10

Compound 10-6 (15 mg, 0.060 mmol) was dissolved in dichloromethane (5 mL), the system was cooled to 0 ° C, and triethylamine (10 mg, 0.100 mmol) and acryloyl chloride (5 mg, 0.055 mmol) were added dropwise. After the addition was completed, the system was heated to room temperature (20 ° C) and reacted for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column: Welch UltimateXB-C18 10×250mm 5μm; mobile phase: [water (0.1% FA)-acetonitrile]; acetonitrile%: 50%-60% 10min, 60% 20min; flow rate 8mL/min). After concentration, compound 10A and compound 10B were obtained.

MS (ESI) m/z (M+H) ⁺ = 586.2.

Compound 10A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ7.83 (d, J＝9.8Hz, 1H), 7.47–7.30 (m, 2H), 7.23 (td, J＝7.5, 1.7Hz, 1H), 7.10 ( td,J＝8.3,6.5Hz,1H),6.96(dd,J＝7.9,1.3Hz,1H),6.74(dd,J＝16.7,10.7Hz,1H),6.58–

6.43(m,2H),6.18(dd,J＝16.8,2.0Hz,1H),5.72(d,J＝10.6Hz,1H),5.24(td,J＝4.5,2.2Hz,1H),4.41(m ,2H),4.06(d,J＝20.7Hz,1H),3.69–3.57(m,1H),3.48–3.35(m,2H),3.07(m,3H),3.073(m,1H),2.92( d,J＝12.3Hz,1H),2.51–2.34(m,1H),1.63(m,3H),1.04(m,3H),0.89(m,3H).

HPLC 93% purity; retention time 6.397 min.

Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; Mobile phase: water (10 mM ammonium bicarbonate solution)-acetonitrile; Acetonitrile: 5%-95% 7 min; Flow rate: 1.2 mL/min.

Compound 10B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ7.83 (d, J＝9.8Hz, 1H), 7.48–7.30 (m, 2H), 7.22 (td, J＝7.5, 1.7Hz, 1H), 7.09 ( td,J＝8.3,6.5Hz,1H),7.01(dd,J＝7.9,1.3Hz,1H),6.74(dd,J＝16.8,10.6Hz,1H),6.62–

6.38 (m, 2H), 6.18 (dd, J = 16.8, 2.0 Hz, 1H), 5.72 (d, J = 10.7 Hz, 1H), 5.24 (td, J = 4.5, 2.2 Hz, 1H), 4.52 (m, 2H), 4.06 (d, J = 19.0 Hz, 1H), 3.72–3.57 (m, 1H), 3.47–3.33 (m, 2H), 3.07 (s, 3H), 3.05–3.00 (m, 1H),, 2.51–2.34 (m, 1H), 1.63 (d, J = 26.2 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H). HPLC 95% purity; retention time 6.580 min

Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; Mobile phase: water (10 mM ammonium bicarbonate solution)-acetonitrile; Acetonitrile: 5%-95% 7 min; Flow rate: 1.2 mL/min.

Example 11: Preparation of Compound 11

Step 1: Preparation of compound 11-1

Compound 10-4 (40 mg, 0.06 mmol) and hydrochloric acid (6N, 1 mL) were added to a mixed solution of methanol (3 mL) and tetrahydrofuran (0.5 mL). The system was heated to 55°C and reacted for 15 min. The system was concentrated to obtain a crude product 11-1.

MS (ESI) m/z (M+H) ⁺ = 518.2.

Step 2: Preparation of compound 11

Compound 11-1 (15 mg, 0.060 mmol) was dissolved in dichloromethane (5 mL), the system was cooled to 0 ° C, and triethylamine (10 mg, 0.100 mmol) and acryloyl chloride (5 mg, 0.055 mmol) were added dropwise. After the addition was completed, the system was heated to room temperature (20 ° C) and reacted for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column: Welch UltimateXB-C18 10×250mm 5μm; mobile phase: [water (0.1% FA)-acetonitrile]; acetonitrile%: 50%-60% 10min, 60% 20min; flow rate 8mL/min) to obtain compound 11A and compound 11B.

Compound 11A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ7.85 (dd, J＝10.0, 6.7Hz, 1H), 7.54–7.40 (m, 2H), 7.33 (td, J＝7.5, 1.8Hz, 1H), 7.17(td,J＝8.3,6.5Hz,1H),7.11–7.04(m,1H),6.83(dd,J＝16.8,10.7Hz,2H),6.59(td,J＝8.5,1.3Hz,2H) ,6.26(dd,J＝16.8,2.0Hz,1H),5.80(ddd,J＝10.7,6.5,2.0Hz,1 H),5.33(td,J＝4.4,2.2Hz,1H),4.70–4.55(m,2H),4.24–4.05(m,1H),3.84–3.61(m,2H),3.53–3.31(m, 2H),3.04(ddd,J＝16.8,12.4,3.7Hz,1H),2.47(td,J＝6.9,2.6Hz,1H),1.73(dd,J＝31.0,6.8Hz,3H),1.11(d ,J＝6.9Hz,3H),0.96(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 572.2.

HPLC 95% purity; retention time 6.180 min.

Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; Mobile phase: [water (10 Mm ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% 7 min; Flow rate: 1.2 mL/min.

Compound 11B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ7.75 (dd, J＝9.9, 6.5Hz, 1H), 7.47–7.30 (m, 2H), 7.23 (td, J＝7.5, 1.7Hz, 1H), 7.16–6.95(m,1H),6.74(ddd,J＝16.8,10.6,2.6Hz,1H),6.55–6.41(m,2H),6.17(dd,J＝16.8,1.9Hz,1H),5.71( ddd,J＝10.7,6.5,2.0Hz,1H),5.24(td,J＝4.5,2.2Hz,1 H),4.59–4.48(m,1H),4.41(s,1H),4.14–3.92(m,1H),3.72–3.54(m,2H),3.46–3.28(m,2H),2.93(ddd, J＝16.6,12.5,3.7Hz,1H),2.30(q,J＝6.9Hz,1H),1.64(dd,J＝30.9,6.8Hz,3H),1.02(d,J＝6.9Hz,3H), 0.89(d,J＝6.9Hz,3H).MS(ESI)m/z(M+H) ⁺ =572.2.

HPLC 95% purity; retention time 6.328 min.

Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; Mobile phase: [water (10 Mm ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% 7 min; Flow rate: 1.2 mL/min.

Example 12: Preparation of Compound 12

Step 1: Preparation of compound 12-2

Compound 1-10 (1.37 g, 3.46 mmol), 12-1 (900 mg, 4.16 mmol), cuprous iodide (395 mg, 0.5 mmol), cesium carbonate (2.26 g, 6.92 mmol) were dissolved in dioxane (20.0 mL), and the system was heated to 100 ° C and stirred for 1 h under a nitrogen atmosphere. The system was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-33%) to obtain compound 12-2.

MS (ESI) m/z (M+H) ⁺ = 576.20.

Step 2: Preparation of compound 12-3

Compound 12-2 (700 mg, 1.2 mmol), compound 2-3 (508 mg, 1.8 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (176 mg, 0.24 mmol), potassium carbonate (323 mg, 2.4 mmol) were dissolved in a mixed solution of dioxane (20 mL) and water (2 mL). Under a nitrogen atmosphere, the system was heated to 100 ° C and stirred for 2 h. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 12-3.

MS (ESI) m/z (M+H) ⁺ = 696.40.

Step 3: Preparation of compound 12-4

Compound 12-3 (50 mg) was dissolved in N, N-dimethylacetamide (1 mL). At room temperature, a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (24%, 0.5 mL) was added thereto. Under a nitrogen atmosphere, the system was heated to 150°C and stirred for 4 h. The system was cooled to room temperature, concentrated, and the residue was dissolved in ethyl acetate (3 mL), washed with water, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 12-4.

MS (ESI) m/z (M+H) ⁺ = 649.40.

Step 4: Preparation of compound 12-5

Compound 12-4 (60.0 mg) and hydrochloric acid (6N, 1 mL) were added to a mixed solution of methanol (0.9 mL) and tetrahydrofuran (0.1 mL). The system was heated to 55°C and reacted for 15 min. The system was concentrated to obtain a crude product 12-5.

MS(ESI) m/z(M+H) ⁺ =505.20.

Step 5: Preparation of compounds 12A and 12B

Compound 12-5 (45 mg, 0.09 mmol) was dissolved in dichloromethane (1 mL), and triethylamine (22 μL, 0.27 mmol) and acryloyl chloride (39 μL, 0.27 mmol) were added dropwise at 0°C. After the addition was completed, the system was heated to room temperature (20°C) and reacted for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the intermediate. The intermediate was then dissolved in tetrahydrofuran (2.0 mL) and water (1.0 mL), and lithium hydroxide (18.9 mg, 0.45 mmol) was added and stirred at room temperature for 30 min. The reaction solution was adjusted to pH 5-6 with dilute hydrochloric acid (3.0 N), and then extracted and concentrated with ethyl acetate to obtain a crude product. The crude product was purified by high performance preparative liquid phase (separation conditions: chromatographic column: Agilent 10 Prep-C8 250×21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 40%-52% in 12 min, 52%-52% in 16 min; flow rate 30 mL/min) to obtain compound 12A and compound 12B.

Compound 12A:

¹ H NMR (400MHz, Chloroform-d) δ7.94 (d, J＝9.9Hz, 1H), 7.61–7.50 (m, 2H), 7.47–7.34 (m, 1H), 7.22 (td, J＝8.3, 6.4Hz,1H),7.05(d,J＝7.5Hz,1H),6.73–6.57(m,3H),6.41( dd,J＝16.8,1.7Hz,1H),5.85(d,J＝10.1Hz,1H),4.68–4.30(m,4H),3.81–3.35(m,4H),3.16(s,1H),2.57 (q,J＝6.8Hz,1H),1.19(d,J＝6.8Hz,3H),0.99(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 559.20.

HPLC 100% purity; retention time 5.483 min.

Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; Mobile phase: [water (10 Mm ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% 7 min; Flow rate: 1.2 mL/min.

Compound 12B:

¹ H NMR (400MHz, Chloroform-d) δ7.93 (d, J＝9.9Hz, 1H), 7.63–7.48 (m, 2H), 7.44–7.33 (m, 1H), 7.25–7.17 (m, 1H) ,7.13(d,J＝7.8Hz,1H),6.70–6.56(m,3H),6.41(dd,J＝16.7,1.7H z,1H),5.84(d,J＝10.4Hz,1H),4.62–4.23(m,3H),4.07–4.00(m,1H),3.79–3.47(m,4H),3.21–3.03(m, 1H), 2.47 (q, J＝6.8Hz, 1H), 1.18 (d, J＝6.8Hz, 3H), 0.98 (d, J＝6.8Hz, 3H).

MS (ESI) m/z (M+H) ⁺ = 559.20.

HPLC 100% purity; retention time 5.555 min.

Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; Mobile phase: [water (10 Mm ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% 7 min; Flow rate: 1.2 mL/min.

Example 13: Preparation of Compound 13

Step 1: Preparation of compound 13-2

Compound 1-12 (766 mg, 1.3 mmol), compound 13-1 (534 mg, 1.56 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (96 mg, 0.13 mmol), potassium carbonate (359 mg, 2.6 mmol) were dissolved in a mixed solution of tetrahydrofuran (20 mL) and water (2 mL), and the system was heated to 80 ° C and stirred for 2 h under a nitrogen atmosphere. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-33%) to obtain compound 13-2.

MS (ESI) m/z (M+H) ⁺ = 770.20.

Step 2: Preparation of compound 13-3

Compound 13-2 (300 mg) was dissolved in N, N-dimethylformamide (6 mL). At room temperature, a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (24%, 3.0 mL) was added thereto. The system was heated to 150°C and stirred for 16 h. The system was cooled to room temperature, concentrated, and the residue was dissolved in ethyl acetate (3 mL), washed with water, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 13-3.

MS (ESI) m/z (M+H) ⁺ = 723.30.

Step 3: Preparation of compound 13-4

Compound 13-3 (214.0 mg) and hydrochloric acid (6N, 4.0 mL) were added to a mixed solution of methanol (3.6 mL) and tetrahydrofuran (0.4 mL). The system was heated to 55°C and reacted for 15 min. The system was concentrated to obtain a crude product 13-4.

MS (ESI) m/z (M+H) ⁺ = 539.20

Step 4: Preparation of compounds 13A and 13B

Compound 13-4 (159 mg, 0.29 mmol) was dissolved in N, N-dimethylformamide (5 mL), and N, N-diisopropylethylamine (0.072 mL, 0.58 mmol), HATU (165.0 mg, 0.435 mmol) and acrylic acid (25.0 mg, 0.348 mmol) were added dropwise at room temperature. After the addition was completed, the system was heated to room temperature (20°C) and reacted for 30 minutes. The reaction solution was washed with water (30 mL), extracted with ethyl acetate (30 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid chromatography (chromatographic column: Agilent 10 Prep-C8 250×21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 25%-40% in 9 min, 40%-45% in 12 min; flow rate 30 mL/min) to obtain compound 13A and compound 13B.

Compound 13A:

¹ H NMR (400MHz, Chloroform-d) δ7.84 (d, J＝9.1Hz, 1H), 7.60 (s, 1H), 7.45 (d, J＝8.6Hz, 1H), 7.40–7.33 (m, 2H ),7.33–7.26(m,2H),7.07(d,J＝7.8Hz,1H),6.70–6.53(m,1H),6.40(d,J＝16.3Hz,1H),5.87–5.76(m ,1H),5.19–4.70(m,1H),4.53–4.29(m,2H),4.19–3.91(m,1H),3.76–3.34(m,3H),3.16(d,J＝12.2Hz,1H ),2.59(p,J＝6.9Hz,1H),2.19(s,3H),1.89–1.63(m,3H),1.15(d,J＝6.8Hz,3H),0.86(d,J＝6.8Hz ,3H).

HPLC 100% purity; retention time 5.069 min.

Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; Mobile phase: [water (10 Mm ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% 7 min; Flow rate: 1.2 mL/min.

Compound 13B:

¹ H NMR (400MHz, Chloroform-d) δ7.84 (d, J＝9.1Hz, 1H), 7.57 (s, 1H), 7.43–7.32 (m, 3H), 7.26–7.16 (m, 2H), 7.11 (d,J＝7.7Hz,1H),6.73–6.55(m,1H),6.40(d,J＝16.5Hz,1H),5.82(dd,J＝10.5,1.7Hz,1H),5.15 –4.68(m,1H),4.42(d,J＝26.9Hz,2H),4.23–3.93(m,1H),3.77–3.42(m,3H),3.12(d,J＝12.2Hz,1H), 2.49(p,J＝6.8Hz,1H),2.15(s,3H),1.75(d,J＝23.3Hz,3H),1.15(d,J＝6.8Hz,3H),0.84(d,J＝6.8 Hz,3H).

HPLC 100% purity; retention time 5.279 min.

Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; Mobile phase: [water (10 Mm ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% 7 min; Flow rate: 1.2 mL/min.

Example 14: Preparation of Compound 14

Step 1: Preparation of compound 14-2

Compound 5-10 (504 mg, 0.84 mmol), compound 14-1 (500 mg, 1.67 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (62 mg, 0.084 mmol), potassium carbonate (232 mg, 1.68 mmol) were dissolved in a mixed solution of tetrahydrofuran (20 mL) and water (2 mL). Under a nitrogen atmosphere, the system was heated to 80 ° C and stirred for 6 h. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-60%) to obtain compound 14-2.

MS (ESI) m/z (M+H) ⁺ = 746.20.

Step 2: Preparation of compound 14-3

Compound 14-2 (200 mg, 0.268 mmol) and triphenylphosphine (213 mg, 0.8 mmol) were added to 1,2-dichloroethane (4 mL), and carbon tetrachloride (130 mg, 0.8 mmol) was added thereto under a nitrogen atmosphere. After the addition, the system was heated to 80°C for 1 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 14-3.

MS (ESI) m/z (M+H) ⁺ = 764.20.

Step 3: Preparation of compound 14-4

Compound 14-3 (40 mg, 0.05 mmol) was dissolved in glacial acetic acid (3 mL), iron powder (30.0 mg, 0.054 mmol) was added thereto, and the system was heated to 80°C for 1 h. The system was concentrated, and the residue was dissolved in ethyl acetate and filtered through diatomaceous earth. The filtrate after filtration was concentrated under vacuum and purified by column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 14-4.

MS(ESI) m/z(M+H) ⁺ =734.20.

Step 4: Preparation of compound 14-5

Compound 14-4 (60 mg, 0.082 mmol), N,N-diisopropylethylamine (0.4 mL) and potassium iodide (14 mg, 0.082 mmol) were dissolved in N,N-dimethylformamide (4 mL), and the system was heated to 120°C for 7 h. The system was cooled to room temperature, water (20 mL) was added thereto, and extracted with EA (15 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 14-5.

MS(ESI) m/z(M+H) ⁺ =698.40.

Step 5: Preparation of compound 14-6

Compound 14-5 (33 mg, 0.047 mmol) was dissolved in tetrahydrofuran (2 mL), and sodium hydride (7.2 mg, 0.18 mmol) was added thereto at 0°C. After the addition, the system was heated to room temperature and stirred for 30 min. Iodomethane (17 mg, 0.12 mmol) was added to the system, and after the addition, the system was stirred at room temperature (20°C) for 1 h. Water (5 mL) was added to the system to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL x 4). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 14-6.

MS (ESI) m/z (M+H) ⁺ = 712.50.

Step 6: Preparation of compound 14-7

Compound 14-6 (40 mg, 0.056 mmol), lithium chloride (10 mg, 0.25 mmol), p-toluenesulfonic acid (45 mg, 0.25 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The system was heated to 120°C and microwaved for 30 min. The system was concentrated, and the residue was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (0.4 mL) was added thereto, and the system was reacted at room temperature (20°C) for 1 h. The system was concentrated to obtain a crude product 14-7.

MS (ESI) m/z (M+H) ⁺ = 598.30.

Step 7: Preparation of compound 14

Compound 14-7 (30 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (25.2 mg, 0.252 mmol) and acryloyl chloride (10 mg, 0.1 mmol) were added dropwise at 0°C. After the addition was completed, the system was heated to room temperature (20°C) and reacted for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column: 5μm F5 LC Column 150x21.2mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile: 20%-35% in 10min; flow rate 30mL/min) to obtain compound 14.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.37(s,1H),8.37(d,J＝4.9Hz,1H),8.33(s,1H),7.82(d,J＝10.4Hz,1H) ,7.78(d,J＝9.9Hz,1H),7.46(d,J＝6.7Hz,1H),7.18(d,J＝4.9Hz,1H),7.11(t,J＝6.2Hz,1H),6.90 –6.75(m,1H),6.40(d,J＝7.2H z,1H),6.11(d,J＝16.7Hz,1H),5.78–5.64(m,1H),4.52–4.04(m,1H),3.29–4.00(m,6H),3.08(s,3H) ,1.97–1.89(m,1H),1.76(s,3H),1.53(d,J＝26.4Hz,3H),1.00(d,J＝6.8Hz,3H),0.88(d,J＝6.6Hz, 3H).

MS (ESI) m/z (M+H) ⁺ = 652.40.

Example 15: Preparation of Compound 15

Step 1: Preparation of compound 15-1

Compound 5-6 (2000 mg, 5.063 mmol), 7-1 (2000 mg, 7.751 mmol), cuprous iodide (470.0 mg, 2.46 mmol), cesium carbonate (3280 mg, 10 mmol) were dissolved in dioxane (30 mL), and the system was heated to 100 ° C and stirred for 1 h under a nitrogen atmosphere. The system was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain compound 15-1.

MS (ESI) m/z (M+H) ⁺ = 633.2.

Step 2: Preparation of compound 15-2

Compound 15-1 (320 mg, 0.517 mmol) and iron powder (115 mg, 2.068 mmol) were dissolved in acetic acid (10 mL), and the system was heated to 80° C. and stirred for 1 h under a nitrogen atmosphere. The system was filtered through celite, and the filtrate was concentrated to obtain a crude product 15-2.

MS (ESI) m/z (M+H) ⁺ = 571.2.

Step 3: Preparation of compound 15-3

Compound 15-2 (100 mg, 0.17 mmol), compound 2-3 (100 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium (50 mg, 0.04 mmol), potassium carbonate (50 mg, 0.34 mmol) were dissolved in a mixed solution of dioxane (5 mL) and water (0.5 mL). Under a nitrogen atmosphere, the system was heated to 100 ° C and stirred for 2 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 15-3.

MS (ESI) m/z (M+H) ⁺ = 691.40.

Step 4: Preparation of compound 15-4

Compound 15-3 (57 mg, 0.07 mmol) and potassium carbonate (30 mg, 0.2 mmol) were dissolved in N,N-dimethylformamide (2 mL). 1-Fluoro-2-bromoethane (30 mg, 0.2 mmol) was added thereto at room temperature (20 ° C). After the addition, the system was heated to 100 ° C and stirred for 1 h under a nitrogen atmosphere. The system was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 15-4.

MS (ESI) m/z (M+H) ⁺ = 737.5.

Step 5: Preparation of compound 15-5

Compound 15-4 (25 mg, 0.035 mmol) and hydrochloric acid (6N, 2 mL) were added to a mixed solution of methanol (2 mL) and tetrahydrofuran (0.2 mL). The system was heated to 55°C and reacted for 1 h. The system was concentrated to obtain a crude compound 15-5.

MS (ESI) m/z (M+H) ⁺ = 593.40.

Step 6: Preparation of compound 15

Compound 15-5 (25 mg, 0.04 mmol) was dissolved in dichloromethane (3 mL), the system was cooled to 0°C, triethylamine (0.1) and acryloyl chloride (4.6 mg, 0.0514 mmol) were added dropwise, and the system was reacted at 0°C for 0.5 h. The system was extracted with water (5 mL) and dichloromethane (3 mL), and the organic phase was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column 5μm F5 LC Column 150x21.2mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile: 15%-35% in 10min, 35%-35% in 16min; flow rate 30mL/min) to obtain compound 15.

¹ H NMR(400MHz, DMSO-d ₆ )δ8.38(d,J＝4.8Hz,1H),7.95(d,J＝8.5Hz,1H),7.30–7.12(m,2H),6.95(dd, J＝16.8,10.6Hz,1H),6.82–6.53(m,2H),6.08(dd,J＝16.8,2.4Hz,1H),5.69(dd,J＝10.5,2.5Hz,1H),4.58–4.43 (m,3 H),3.96(dd,J＝23.4,4.0Hz,1H),3.69(dd,J＝14.2,4.3Hz,1H),3.50–3.32(m,3H),2.83–2.71(m,1H),2.71 –2.54(m,1H),1.81(d,J＝55.9Hz,3H),1.48(dd,J＝6.8,2.1Hz,3H),1.08–0.63(m,6H).

MS (ESI) m/z (M+H) ⁺ = 647.4.

HPLC 90% purity; retention time 5.224 min.

Separation conditions: Chromatographic column: Waters Xbridge C18 3.5μm, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; flow rate: 1.2mL/min.

Example 16: Preparation of Compound 16

Step 1: Preparation of compound 16-1

Under nitrogen protection, compound 3-14 (100 mg, 140.50 μmol) was dissolved in 1,2-dichloroethane (3 mL), triphenylphosphine (112 mg, 427.01 μmol) and carbon tetrachloride (80 mg, 520.08 μmol, 0.05 mL) were added in sequence, and the temperature was raised to 80°C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative silica gel plate chromatography (ethyl acetate/petroleum ether (v/v) = 100%) to obtain compound 16-1.

MS (ESI) m/z (M+H) ⁺ = 730.3.

Step 2: Preparation of compound 16-2

Compound 16-1 (80 mg, 109.56 μmol) was dissolved in acetic acid (1 mL), iron powder (31 mg, 555.11 μmol) was added, and the temperature was raised to 80°C and stirred for 1 h. The reaction solution was diluted with ethyl acetate (10 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was dissolved in ethyl acetate (10 mL), washed with saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative silica gel plate chromatography (ethyl acetate/petroleum ether (v/v) = 100%) to obtain compound 16-2.

MS (ESI) m/z (M+H) ⁺ = 700.2.

Step 3: Preparation of compound 16-3

Compound 16-2 (60 mg, 85.69 μmol) was dissolved in N,N-dimethylformamide (1 mL), and diisopropylethylamine (37.10 mg, 287.06 μmol, 0.05 mL) was added, and the reaction was heated to 120°C in a sealed tube and stirred for 6 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative silica gel plate chromatography (methanol/dichloromethane (v/v) = 1/15) to obtain compound 16-3.

MS (ESI) m/z (M+H) ⁺ = 664.1.

Step 4: Preparation of compound 16-4

Compound 16-3 (40 mg, 60.27 μmol) was dissolved in tetrahydrofuran (1 mL), and sodium hydride (5 mg, 125.01 μmol, 60%) and iodomethane (10 mg, 70.45 μmol) were added in sequence, and the reaction was stirred at 25°C for 1 h. The reaction solution was quenched with 2 drops of saturated ammonium chloride solution, diluted with ethyl acetate (20 mL), washed with water (20 mL) and saturated sodium chloride solution (20 mL) in sequence, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 16-4.

MS (ESI) m/z (M+H) ⁺ = 678.4.

Step 5: Preparation of compound 16-5

Compound 16-4 (40 mg, 59.02 μmol) was dissolved in dichloromethane (1 mL), and boron tribromide (73.93 mg, 295.09 μmol, 28.43 μL) was added, and the reaction was stirred at 20°C for 3 h. The reaction solution was quenched with methanol (10 mL), stirred for 10 min, and concentrated under reduced pressure to obtain crude product 16-5. MS (ESI) m/z (M+H) ⁺ = 564.0.

Step 6: Preparation of compound 16

Compound 16-5 (50 mg, 77.58 μmol) was dissolved in tetrahydrofuran (1 mL), and saturated sodium bicarbonate solution (2.16 g, 25.71 mmol, 1 mL) and acrylic anhydride (11 mg, 87.23 μmol) were added in sequence. The reaction was stirred at 20 ° C for 1 h. Methanol (1 mL) and potassium carbonate aqueous solution (2M, 1 mL) were added and continued to stir for 1.5 h. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL x2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by high-efficiency preparative liquid phase separation (separation conditions: chromatographic column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 36%-66%, 9.5min). Compound 16A (peak 1) and compound 16B (peak B) were obtained.

Compound 16A:

¹ H NMR (400MHz, MeOD) δ8.41 (d, J＝5.1Hz, 1H), 7.55 (br d, J＝9.7Hz, 1H), 7.28-7.16 (m, 2H), 6.84 (dd, J＝ 10.7,16.6Hz,1H),6.71-6.57(m,2H),6.28(dd,J＝1.9,16.6Hz,1H),5.82(br d,J＝10.8Hz,1H),5.04-4.91(m, 2H),4.60-4.53(m,1H),4.13(br s,1H),3.74(br s,1H),3.59-3.43(m,2H),3.15(s,3H),3.02(br s,1H),2.81-2.57(m,1H),2.05(d,J＝15.7Hz,3H),1.83-1.65(m,3H),1.18-1.06(m,6H).MS(ESI)m/ z(M+H) ⁺ =618.2.

HPLC 97% of purity; Retention time: 4.00min+4.051min.

Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: [water (0.02% ammonia solution)-acetonitrile]; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 0.8mL/min.

Compound 16B:

¹ H NMR (400MHz, MeOD) δ8.41 (d, J＝5.1Hz, 1H), 7.54 (br d, J＝9.0Hz, 1H), 7.30-7.14 (m, 2H), 6.84 (dd, J＝ 10.9,16.6Hz,1H),6.71-6.55(m,2H),6.35-6.21(m,1H),5.81(brd,J＝9.5Hz,1H),5.01-4.90(m,2H),4.66-4.50 (m,1H),4.15(br d,J＝15.4Hz,1H),3.71(br s,1H),3.62-3.42(m,2H),3.14(s,3H),3.01(br s,1H),2.81-2.56(m,1H),2.12-1.95(m,3H),1.83-1.61(m,3H),1.19-1.02(m,6H).

MS (ESI) m/z (M+H) ⁺ = 618.3.

HPLC 94% of purity; Retention time: 4.082min.

Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: [water (0.02% ammonia solution)-acetonitrile]; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 0.8mL/min.

Step 7: Preparation of compounds 16A-1 and 16A-2

The diastereoisomer compound 16A was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: [CO ₂ -isopropanol (0.1% ammonia water)]; isopropanol%: 35%). After concentration, compound 16A-1 and compound 16A-2 were obtained.

Compound 16A-1:

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.42 (br d, J＝4.9Hz, 1H), 7.40 (br s, 1H), 7.29-7.07 (m, 2H), 6.85 (br d, J＝ 10.3Hz,1H),6.75-6.53(m,2H),6.16(br d,J＝9.0Hz,1H),5.74(brd,J＝10.0Hz,1H),4.79(br s,1H),4.46( br d,J＝14.4Hz,1H),4.16(br d,J＝14.2Hz,1H),3.89(br d,J＝14.7Hz,1H),3.51-3.36(m,2H),3.23-3.15(m,2H),3.08(s,2H),2.98-2.85(m,2H),2.66(br d,J ＝1.7Hz,1H),1.90(s,3H),1.72-1.47(m,3H),1.26-0.88(m,6H).

MS (ESI) m/z (M+H) ⁺ = 618.3.

SFC retention time: 1.516 min.

Separation conditions: Column: Chiralpak AD-3 50x4.6mm ID, 3μm; Column temperature: 35°C; Mobile phase: CO ₂ -isopropanol (0.05% DEA); Isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; Flow rate: 4mL/min.

Compound 16A-2:

¹ H NMR (400MHz, METHANOL-d ₄ ) δ8.41 (br d, J＝4.9Hz, 1H), 7.55 (br d, J＝11.0Hz, 1H), 7.30-7.10 (m, 2H), 6.84 ( br dd,J＝10.5,16.6Hz,1H),6.71-6.51(m,2H),6.27(br dd,J＝1.8,16.8Hz,1H),5.82(br d,J＝10.6Hz,1H), 4.96-4.92(m,1H),4.61(br s,2H),4.26-4.13(m,1H),3.72(br s,1H),3.52-3.38(m,2H),3.14(s,3H), 2.99(br s,1H),2.62(td,J=6.8,13.7Hz,1H),2.06(s,3H),1.85-1.59(m,3H),1.39-1.03(m,6H).

MS (ESI) m/z (M+H) ⁺ = 618.3.

SFC retention time: 1.644 min.

Separation conditions: Column: Chiralpak AD-3 50x4.6mm ID, 3μm; Column temperature: 35°C; Mobile phase: CO ₂ -isopropanol (0.05% DEA); Isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; Flow rate: 4mL/min.

Step 8: Preparation of compounds 16B-1 and 16B-2

The diastereoisomer compound 16B was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: [CO ₂ -isopropanol (0.1% ammonia water)]; isopropanol%: 35%). After concentration, compound 16B-1 and compound 16B-2 were obtained.

Compound 16B-1:

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.43 (br d, J＝4.9Hz, 1H), 7.41 (br s, 1H), 7.29-7.14 (m, 2H), 6.86 (br d, J＝ 11.0Hz,1H),6.75-6.59(m,2H),6.19(br s,1H),5.75(br d,J＝10.8Hz,1H),4.80(br s,1H),4.47(br d,J ＝14.4Hz,1H),4.15(br s,1H),3.90(br d,J＝17.1Hz,1H),3.55-3.40(m,2H),3.21(br d,J＝11.2Hz,2H),3.09(s,3H),2.97-2.81(m,2H),1.89(s,3H),1.68-1.51(m,3H),1.19-0.90(m,6H) .

MS (ESI) m/z (M+H) ⁺ = 618.3.

SFC retention time: 1.521 min.

Separation conditions: Column: Chiralpak AD-3 50x4.6mm ID, 3μm; Column temperature: 35°C; Mobile phase: CO ₂ -isopropanol (0.05% DEA); Isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; Flow rate: 4mL/min.

Compound 16B-2:

¹ H NMR (400MHz, METHANOL-d ₄ ) δ8.41 (br d, J＝5.1Hz, 1H), 7.55 (br d, J＝10.4Hz, 1H), 7.34-7.13 (m, 2H), 6.84 ( br dd,J＝10.7,16.6Hz,1H),6.73-6.53(m,2H),6.28(br dd,J＝1.8,16.8Hz,1H),5.81(br s,1H),4.98-4.93(m ,1H),4.61(br s,2H),4.15(br s,1H),3.72(br s,1H),3.47(br d,J＝13.9Hz,2H),3.15(s,3H),3.06-2.94(m,1H),2.68-2.57(m,1H),2.08(s,3H),1.87-1.63(m,3H) ,1.36-1.01(m,6H).

MS (ESI) m/z (M+H) ⁺ = 618.3.

SFC retention time: 1.652 min.

Separation conditions: Column: Chiralpak AD-3 50x4.6mm ID, 3μm; Column temperature: 35°C; Mobile phase: CO ₂ -isopropanol (0.05% DEA); Isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; Flow rate: 4mL/min.

Example 17: Preparation of Compound 17

Step 1: Preparation of compound 17-2

Compound 1-12 (450 mg, 0.76 mmol), 17-1 (240 mg, 0.92 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (65 mg, 0.076 mmol), potassium carbonate (210 mg, 1.5 mmol) were dissolved in a mixed solution of dioxane (20 mL) and water (2 mL), and the system was heated to 90 ° C and stirred for 3 h under a nitrogen atmosphere. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain compound 17-2.

MS (ESI) m/z: (M+H) ⁺ =770.1.

Step 2: Preparation of compound 17-3

Compound 17-2 (50 mg, 0.065 mmol) was dissolved in N, N-dimethylacetamide (5 mL). At room temperature, a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (24%, 0.65 mL) was added thereto. Under a nitrogen atmosphere, the system was heated to 160°C and stirred for 8 h. The system was cooled to room temperature, concentrated, and the residue was dissolved in ethyl acetate (3 mL), washed with water, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-40%) to obtain compound 17-3.

MS (ESI) m/z: (M+H) ⁺ =723.3.

Step 3: Preparation of compound 17-4

Compound 17-3 (30 mg, 0.041 mmol) was dissolved in methanol (3 mL), and concentrated hydrochloric acid (12N, 2 mL) was added. After the addition, the system was heated to 70°C for 3 h. The system was concentrated to obtain a yellow oil 17-4, which was directly used in the next step without further purification. MS (ESI) m/z (M+H) ⁺ = 539.2.

Step 4: Preparation of compound 17-6

Compound 17-5 (2 g, 15.2 mmol) was dissolved in trifluoroacetic acid (10 mL), and N-bromosuccinimide (3 g, 16.7 mmol) was added thereto. After the addition, the system was heated to 80°C and stirred for 1 h under closed conditions. The system was concentrated, saturated sodium bicarbonate aqueous solution was added, pH>7 was adjusted, and the system was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (methanol/dichloromethane (v/v) = 0-10%) to obtain compound 17-6.

MS (ESI) m/z: (M+H) ⁺ = 212.8.

Step 5: Preparation of compound 17-7

Compound 17-6 (350 mg, 1.66 mmol) was dissolved in tetrahydrofuran (20 mL), and tetrahydropyran (420 mg, 5.0 mmol) and p-toluenesulfonic acid (65 mg, 0.33 mmol) were added thereto. After the addition, the system was heated to 80°C and refluxed for 24 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (methanol/dichloromethane (v/v) = 0-1%) to obtain compound 17-7.

MS (ESI) m/z: (M+H) ⁺ =297.0.

Step 6: Preparation of compound 17-1

Compound 17-7 (300 mg, 1.0 mmol), biboric acid pinacol ester (500 mg, 2.0 mmol), potassium acetate (300 mg, 3.0 mmol) and ditricyclohexylphosphine palladium dichloride (74 mg, 0.1 mmol) were dissolved in a mixed solvent of N, N-dimethylacetamide (10 mL) and water (1 mL). Under a nitrogen atmosphere, the system was heated to 155 ° C and stirred for 2 h. After the system was cooled to room temperature, it was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 17-1, which was directly used in the next step without further purification.

MS (ESI) m/z: (M+H) ⁺ = 261.0.

Step 7: Preparation of compound 17

Compound 17-4 (20 mg, 0.037 mmol) was dissolved in dichloromethane (1 mL). The system was cooled to 0 ° C at room temperature, and triethylamine (10 mg, 0.1 mmol) and acryloyl chloride (5 mg, 0.05 mmol) were added dropwise. After the addition was completed, the system was heated to room temperature (20 ° C) and reacted for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column Agilent 10 Prep-C8250×21.2 mm; column temperature: 25 ° C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile: 20%-40% in 12 min; flow rate 30 mL/min) to obtain compound 17.

MS (ESI) m/z (M+H) ⁺ = 593.3.

HPLC: 95%, 4.875min+5.087min.

Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; Mobile phase: [water (10 mM ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% 7 min; Flow rate: 1.2 mL/min.

Example 18: Preparation of Compounds 18A-1/18A-2/18B-1 and 18B-2

Step 1: Preparation of compound 18-1

At 0℃, under nitrogen protection, compound 4-8 (8.6g, 26.24mmol) was dissolved in acetonitrile (40mL), and cuprous iodide (5.05g, 26.51mmol), potassium iodide (8.84g, 53.27mmol) and tert-butyl nitrite (5.66g, 54.85mmol, 6.52mL) were added in sequence, and the reaction temperature was raised to 80℃ and stirred for 2h. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (80mL), washed with saturated sodium thiosulfate solution (80mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/0 to 2/3) to obtain compound 18-1.

¹ H NMR (400MHz, CDCl ₃ ) δ7.77 (d, J = 1.5Hz, 1H), 7.46-7.38 (m, 1H), 6.87-6.77 (m, 2H), 3.98 (s, 3H), 3.80 ( s,3H).

Step 2: Preparation of compound 18-2

Under nitrogen protection, compound 18-1 (6.5 g, 14.82 mmol) and 2-isopropyl-4-methyl-pyridin-3-amine (2.60 g, 17.31 mmol) were dissolved in toluene (10 mL), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (950 mg, 1.64 mmol), tris(dibenzylideneacetone)dipalladium (1.5 g, 1.64 mmol) and cesium carbonate (14.49 g, 44.46 mmol) were added in sequence, and the reaction temperature was raised to 100 ° C and stirred for 16 h. The reaction solution was diluted with ethyl acetate (100 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/0 to 2/3) to obtain compound 18-2.

MS (ESI) m/z (M+H) ⁺ = 460.

¹ H NMR (400MHz, CDCl ₃ ) δ9.08 (br s, 1H), 8.29 (d, J = 4.9Hz, 1H), 8.04-7.92 (m, 1H), 7.36-7.28 (m, 1H), 6.94 (t,J＝5.4Hz,1H),6.78-6.68(m,2H),3.98(s,3H),3.74(d,J＝17.4Hz,3H),3.52-3.41(m,1H),2.20( s,3H),1.27-1.24(m,3H),1.21(d,J=6.6Hz,3H).

Step 9: Preparation of compound 18-3

At 0°C, compound 18-2 (3.2 g, 6.94 mmol) was dissolved in N, N-dimethylformamide (30 mL), sodium hydride (1.39 g, 34.71 mmol, 60%) was added, stirred for 20 min, and then acetyl chloride (2.73 g, 34.71 mmol, 2.48 mL) was added, and the reaction temperature was raised to 25°C and stirred for 16 h. The reaction solution was quenched with water (100 mL), saturated potassium carbonate solution (100 mL) was added, stirred for 1 h, extracted with ethyl acetate (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/0 to 0/1) to obtain compound 18-3.

MS (ESI) m/z (M+H) ⁺ = 503.1.

¹ H NMR (400MHz, CDCl ₃ ) δ8.49-8.43(m,1H),7.85(s,1H),7.37-7.30(m,1H),7.07-7.01(m,1H),6.80-6.64(m ,2H),4.04-3.89(m,3H),3.80-3.74(m,1H),3.74-3.42(m,4H),2.33(br d,J＝3.1Hz,3H),1.97(br d,J ＝4.9Hz,3H),1.29(br d,J＝6.4Hz,3H),0.88-0.71(m,3H).

Step 10: Preparation of compound 18-4

Under nitrogen protection, compound 18-3 (580 mg, 1.15 mmol) was dissolved in toluene (10 mL), potassium tert-butoxide (1.0 M tetrahydrofuran solution, 3.74 mL) was added, and the reaction was stirred at 25 ° C for 30 min. The reaction solution was quenched with water (20 mL), 1.0 M hydrochloric acid was added to adjust the pH to 7.0, and extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product 18-4, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 471.2.

¹ H NMR (400MHz, Chloroform-d) δ8.64-8.51(m,1H),8.01(s,1H),7.39-7.31(m,1H),7.13(t,J＝4.1Hz,1H),6.79 -6.70(m,2H),6.43(s,1H),3.75-3.66(m,3H),2.85-2.71(m,1H),2.12-2.07(m,3H),1.26-1.22(m,3H) ,1.17-1.11(m,3H).

Step 11: Preparation of compound 18-5

Under nitrogen protection, compound 18-4 (500 mg, 1.06 mmol) was dissolved in acetic acid (10 mL), and concentrated nitric acid (1.23 g, 19.51 mmol, 878.20 μL) was added, and the reaction temperature was raised to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure to remove most of the acetic acid, cooled to 0°C, added with water (50 mL), filtered, and the filter cake was dried under vacuum to obtain the crude product 18-5, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 516.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.57–8.55(m,1H),8.06(s,1H),7.67-7.38(m,2H),7.03-6.77(m,2H),3.74-3.61 (m,1H),3.58-3.50(m,3H),2.53-2.51(m,3H),2.15(br d,J＝6.0Hz,1H),1.33-0.94(m,6H).

Step 12: Preparation of compound 18-6

Under nitrogen protection, compound 18-5 (600 mg, 1.16 mmol) was dissolved in acetonitrile (10 mL), and diisopropylethylamine (901.86 mg, 6.98 mmol, 1.22 mL) and phosphorus oxychloride (534.98 mg, 3.49 mmol, 324.23 μL) were added in sequence, and the reaction temperature was raised to 80 ° C and stirred for 2 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/0 to 1/1) to obtain compound 18-6.

MS (ESI) m/z (M+H) ⁺ = 534.

¹ H NMR (400MHz, Chloroform-d) δ8.57-8.51(m,1H),8.17(t,J＝1.7Hz,1H),7.43-7.34(m,1H),7.09(t,J＝4.2Hz ,1H),6.81-6.71(m,2H),3.81-3.65(m,4H),2.77-2.67(m,1H),2.13(d,J＝6.0Hz,3H),1.35-1.17(m,6H ).

Step 13: Preparation of compound 18-7

Under nitrogen protection, compound 18-6 (320 mg, 598.87 μmol) was dissolved in acetonitrile (8 mL), and diisopropylethylamine (387.76 mg, 3.00 mmol, 522.59 μL) and compound 1-11 (206.88 mg, 898.31 μmol) were added in sequence, and the reaction temperature was raised to 80 ° C and stirred for 1 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/0 to 2/3) to obtain compound 18-7. MS (ESI) m/z (M+H) ⁺ = 728.2.

Step 14: Preparation of compound 18-8

Under nitrogen protection, compound 18-7 (350 mg, 480.65 μmol) was dissolved in N-methylpyrrolidone (10 mL), and 4A molecular sieves (500 mg) and lithium bis(trimethylsilyl)amide (1M tetrahydrofuran solution, 1.44 mL) were added in sequence. The reaction temperature was raised to 130°C and stirred for 16 h. The reaction solution was concentrated under reduced pressure to remove the solvent, ethyl acetate (50 mL) was added to dilute, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (dichloromethane/methanol (v/v) = 10/1) to obtain compound 18-8.

MS (ESI) m/z (M+H) ⁺ = 681.3.

Step 15: Preparation of compound 18-9

Under nitrogen protection, compound 18-8 (150 mg, 220.21 μmol) was dissolved in dichloromethane (3 mL), and boron tribromide (275.84 mg, 1.10 mmol, 106.09 μL) was added, and the reaction was stirred at 25 ° C for 2 h. The reaction solution was quenched by adding methanol (10 mL), stirred for 10 min, and concentrated under reduced pressure to obtain crude product 18-9, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 567.1.

Step 16: Preparation of compounds 18A and 18B

Compound 18-9 (128.49 mg, 226.60 μmol) was dissolved in tetrahydrofuran (5 mL), and sodium bicarbonate (3.79 g, 45.14 mmol, 1.76 mL) and acrylic anhydride (28.58 mg, 226.60 μmol) were added in sequence. The reaction was stirred at 25 ° C for 30 min, methanol (2 mL) and saturated potassium carbonate aqueous solution (2 mL) were added, and stirring was continued for 1 h. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by high-efficiency preparative liquid phase separation (separation conditions: chromatographic column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile%: 50%-80%, 9min), to obtain:

Compound 18A (HPLC retention time 3.747, 3.871 min).

Compound 18B (HPLC retention time 3.835, 3.916 min).

HPLC analysis conditions: chromatographic column: Xbridge Shield RP-18, 5 μm, 2.1*50 mm; mobile phase: [water (0.02% ammonia solution v/v)-acetonitrile]; acetonitrile%: 10%-80%, column temperature: 50°C.

Compound 18A:

MS (ESI) m/z (M+H) ⁺ = 621.2.

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.42 (d, J = 4.9 Hz, 1H), 7.89 (br s, 1H), 7.26-7.17 (m, 2H), 6.83 (dd, J = 10.6, 16.8Hz,1H),6.69-6.58(m,2H),6.27(br d,J＝16.8Hz,1H),5.82(br d,J＝10.1Hz,1H),5.04-4.93(m,1H), 4.72-4.10(m,4H),3.74(br s,1H),3.65-3.44(m,2H),3.14(br s,1H),2.66(td,J＝6.6,13.8Hz,1H),2.12-2.01(m,3H),1.84-1.64(m,3H),1.19-1.03(m,6H).

Compound 18B:

MS (ESI) m/z (M+H) ⁺ = 621.2.

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.42 (d, J = 4.9 Hz, 1H), 7.89 (br s, 1H), 7.27-7.16 (m, 2H), 6.83 (dd, J = 10.8, 16.8Hz,1H),6.71-6.58(m,2H),6.27(dd,J＝1.7,16.9Hz,1H),5.82(br d,J＝10.6Hz,1H),5.04-4.92(m,1H) ,4.73-4.10(m,4H),3.74(br s,1H),3.66-3.47(m,2H),3.15(br d,J＝10.4Hz,1H),2.77-2.58(m,1H),2.05(d,J＝2.9Hz,3H),1.84-1.62(m,3H),1.17-1.02(m,6H).

Step 17: Isolation of compounds 18A-1 and 18A-2

Compound 18A was separated and purified by SFC (separation conditions: chromatographic column: REGIS (s, s) WHELK-O1 (250mm*30mm, 5μm); mobile phase: [supercritical carbon dioxide-ethanol]; ethanol%: 50%-50%) to obtain:

Compound 18A-1 (HPLC retention time 8.29 min; ee: 99.24%).

Compound 18A-2 (HPLC retention time 8.37 min; ee: 99.38%).

HPLC analysis conditions: chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; mobile phase: [water (0.06875% trifluoroacetic acid solution v/v)-acetonitrile (0.0625% trifluoroacetic acid solution v/v)]; acetonitrile%: 10%-80%, column temperature: 40°C.

SFC chiral analysis conditions: chromatographic column: (S,S)-Whelk-O1 100*4.6mm, 3μm; mobile phase: [supercritical carbon dioxide-ethanol (0.05% diethylamine solution v/v)]; ethanol%: 40%-40%, column temperature: 35°C.

Compound 18A-1:

MS (ESI) m/z (M+H) ⁺ = 621.3.

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.42 (d, J = 5.1 Hz, 1H), 7.89 (br s, 1H), 7.27-7.15 (m, 2H), 6.83 (dd, J = 10.7, 16.6Hz,1H),6.72-6.56(m,2H),6.28(dd,J＝1.8,16.8Hz,1H),5.82(br d,J＝10.1Hz,1H),5.05-4.94(m,1H),4.70-4.35(m,3H),3.83-3.68(m,1H),3.65-3.51(m,2H),3.20-3.13( m,1H),2.79-2.66(m,1H),2.13-2.02(m,3H),1.83-1.65(m,3H),1.16(br d,J＝6.6Hz,3H),1.11-1.00(m ,3H).

Compound 18A-2:

MS (ESI) m/z (M+H) ⁺ = 621.2.

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.42 (d, J = 4.9 Hz, 1H), 7.89 (br s, 1H), 7.28-7.17 (m, 2H), 6.83 (dd, J = 10.6, 16.8Hz,1H),6.69-6.58(m,2H),6.27(dd,J＝1.8,16.8Hz,1H),5.82(br d,J＝11.0Hz,1H),5.03-4.94(m,1H) ,4.70-4.34(m,3H),3.76(br d,J＝11.5Hz,1H),3.64-3.48(m,2H),3.14(br d,J＝9.3Hz,1H),2.66(td,J＝6.8,13.6Hz,1H),2.06(s,3H),1.80-1.67(m,3H),1.14(d,J＝6.8Hz,3H ),1.11(d,J＝6.8Hz,3H).

Step 18: Isolation of compounds 18B-1 and 18B-2

Compound 18B was separated and purified by SFC (separation conditions: chromatographic column: REGIS (s, s) WHELK-O1 (250mm*30mm, 5μm); mobile phase: [supercritical carbon dioxide-ethanol]; ethanol%: 50%-50%) to obtain:

Compound 18B-1 (HPLC retention time 8.59 min; ee: 100%).

Compound 18B-2 (HPLC retention time 8.53 min; ee: 100%).

HPLC analysis conditions: chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; mobile phase: [water (0.06875% trifluoroacetic acid solution v/v)-acetonitrile (0.0625% trifluoroacetic acid solution v/v)]; acetonitrile%: 10%-80%, column temperature: 40°C.

SFC chiral analysis conditions: chromatographic column: (S,S)-Whelk-O1 100*4.6mm, 3μm; mobile phase: [supercritical carbon dioxide-ethanol (0.05% diethylamine solution v/v)]; ethanol%: 40%-40%, column temperature: 35°C.

18B-1:

MS (ESI) m/z (M+H) ⁺ = 621.2.

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.42 (d, J = 5.1 Hz, 1H), 7.88 (br s, 1H), 7.27-7.15 (m, 2H), 6.83 (dd, J = 10.8, 16.8Hz,1H),6.70-6.55(m,2H),6.27(dd,J＝1.7,16.9Hz,1H),5.82(br d,J＝9.9Hz,1H),5.04-4.93(m,1H) ,4.70-4.34(m,3H),3.75(br d,J＝10.8Hz,1H),3.65-3.45(m,2H),3.17(br d,J＝8.6Hz,1H),2.75-2.63(m,1H),2.09-1.99(m,3H),1.81-1.65(m,3H),1.14(br d,J＝6.6Hz,3H), 1.11-1.04(m,3H).

18B-2:

MS (ESI) m/z (M+H) ⁺ = 621.2.

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.42 (br d, J＝5.1Hz, 1H), 7.89 (br s, 1H), 7.29-7.17 (m, 2H), 6.83 (br dd, J＝ 10.9,16.6Hz,1H),6.71-6.55(m,2H),6.27(br d,J＝16.8Hz,1H),5.82(br d,J＝9.5Hz,1H),5.03-4.92(m,1H ),4.68-4.35(m,3H),3.75(br d,J＝11.2Hz,1H),3.64-3.44(m,2H),3.14(br d,J＝8.4Hz,1H),2.65(td,J＝6.4,13.1Hz,1H),2.06(s,3H),1.84-1.66(m,3H),1.19-1.12(m,3H),1.11 -0.97(m,3H).

Example 19: Preparation of Compound 19

Step 1: Preparation of compound 19-3

At room temperature (20°C), compound 19-1 (9.5 g, 57.93 mmol), compound 19-2 (29.20 g, 173.79 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (3.39 g, 4.63 mmol) and potassium carbonate (24.02 g, 173.79 mmol) were dissolved in 1,4-dioxane (150 mL) and water (30 mL). Under nitrogen atmosphere, the system was heated to 100°C and stirred for 12 h. The system was cooled to room temperature, concentrated to remove most of the solvent, and then water (100 mL) was added thereto. The mixture was extracted with ethyl acetate (80 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 19-3.

¹ H NMR (400MHz, DMSO-d ₆ )8.39(s,1H),5.57-5.51(m,2H),5.42(s,2H),4.89(s,2H),2.06(s,6H).MS( ESI)m/z(M+H) ⁺ =175.9.

Step 2: Preparation of compound 19-4

Compound 19-3 (10.37 g, 59.18 mmol) was dissolved in methanol (50 mL), and 10% palladium on carbon (1 g) was added thereto under a nitrogen atmosphere. After the addition, the system was replaced with hydrogen. Under a hydrogen atmosphere (15 psi), the system was stirred at room temperature (25°C) for 12 h. The system was filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane (100 mL), washed with 2M aqueous hydrochloric acid solution (50 mL), the aqueous phase was adjusted to pH 9-10 with sodium hydroxide, and then extracted with dichloromethane (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-4, which was directly used in the next step without further purification.

¹ H NMR (400MHz, DMSO-d ₆ )8.31 (s, 1H), 5.04 (s, 2H), 3.25-3.16 (m, 2H), 1.13 (d, J = 6.5Hz, 12H).MS (ESI) m/z(M+H) ⁺ =180.0.

Step 3: Preparation of compound 19-5

At room temperature (20°C), compound 3-8 (4.8 g, 11.37 mmol), compound 19-4 (2.65 g, 14.78 mmol), tris(dibenzylideneacetone)dipalladium (1.2 g, 1.31 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (750 mg, 1.30 mmol) and cesium carbonate (11.11 g, 34.11 mmol) were dissolved in toluene (40 mL). Under a nitrogen atmosphere, the system was heated to 100°C and stirred for 16 h. The system was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 19-5.

¹ H NMR (400MHz, Chloroform-d) δ8.97 (s, 1H), 8.90 (br d, J = 3.7Hz, 1H), 7.67 (brdd, J = 2.0, 9.5Hz, 1H), 7.39-7.30 ( m,1H),6.84-6.65(m,2H),3.99(s,3H),3.72(s,3H),3.45-3.31(m,2H),1.37-0.89(m,12H).

MS (ESI) m/z (M+H) ⁺ = 474.4.

Step 4: Preparation of compound 19-6

Compound 19-5 (3.75 g, 7.92 mmol) was dissolved in N,N-dimethylformamide (40 mL). Sodium hydride (1.90 g, 47.52 mmol, 60% purity) was added in batches at 0°C. After the system was reacted at 0°C for 20 min, acetyl chloride (3.73 g, 47.52 mmol, 3.39 mL) was added dropwise. After the addition, the system was reacted at room temperature (25°C) for 16 h under nitrogen atmosphere. Water (20 mL) was added to the system to quench the reaction. A saturated potassium carbonate aqueous solution was added to the system. After stirring at room temperature (25°C) for 1 h, the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-100%) to obtain compound 19-6.

MS (ESI) m/z (M+H) ⁺ = 516.3.

Step 5: Preparation of compound 19-7

At room temperature (20°C), compound 19-6 (1 g, 1.94 mmol) was dissolved in toluene (10 mL), and potassium tert-butoxide (1 M, 6.28 mL) was added thereto. After the addition, the system was reacted at room temperature (25°C) for 0.5 h under a nitrogen atmosphere. Water (20 mL) was added to the system to quench the reaction, and the pH was adjusted to neutral with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-7, which was directly used in the next step without further purification.

¹ H NMR (400MHz, Chloroform-d) δ11.25 (br s, 1H), 9.48-9.16 (m, 1H), 7.53 (dd, J＝1.4, 8.5Hz, 1H), 7.36 (dt, J＝6.7 ,8.4Hz,1H),6.80-6.72(m,2H),6.53(s,1H),3.72(s,3H),2.88-2.74(m,2H),1.23(dd,J＝6.7,10.9Hz, 6H), 1.14 (dd, J＝6.7, 11.6Hz, 6H).

MS (ESI) m/z (M+H) ⁺ = 484.0.

Step 6: Preparation of compound 19-8

Compound 19-7 (1.3 g, 2.69 mmol) was dissolved in glacial acetic acid (15 mL). Nitric acid (3.11 g, 49.42 mmol, 2.22 mL) was added dropwise to the system at room temperature (20 ° C). After the addition was completed, the system was heated to 80 ° C and stirred for 2 h. After the system was cooled to room temperature, most of the glacial acetic acid was removed by concentration, and the residue was poured into ice water (50 mL). The precipitate was precipitated and filtered. The filter cake was washed with water and dried to obtain compound 19-8, which was directly used in the next step without further purification.

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.02 (s, 1H), 7.80 (br d, J = 9.0Hz, 1H), 7.51-7.40 (m, 1H), 6.99-6.85 (m, 2H) ,3.73-3.63(m,3H),3.17(s,1H),2.91-2.75(m,2H),1.33-0.90(m,12H).

MS (ESI) m/z (M+H) ⁺ = 529.0.

Step 7: Preparation of compound 19-9

Compound 19-8 (800 mg, 1.51 mmol) and N,N-diisopropylethylamine (1.17 g, 9.08 mmol, 1.58 mL) were dissolved in acetonitrile (10 mL). Phosphorus oxychloride (696.32 mg, 4.54 mmol, 422.01 μL) was added thereto at room temperature. After the addition, the system was heated to 80°C and stirred for 2 h. The system was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-100%) to obtain compound 19-9.

¹ H NMR (400MHz, Chloroform-d) δ9.18 (s, 1H), 7.88 (br d, J = 8.6Hz, 1H), 7.48-7.34 (m, 1H), 6.87-6.68 (m, 2H), 3.82-3.66(m,3H),2.89-2.61(m,2H),1.39-1.07(m,12H).

MS (ESI) m/z (M+H) ⁺ = 547.0.

Step 8: Preparation of compound 19-10

Compound 19-9 (400 mg, 731.36 μmol), 1-11 (252.65 mg, 1.10 mmol) and N,N-diisopropylethylamine (473.56 mg, 3.66 mmol, 638.22 μL) were dissolved in acetonitrile (10 mL). Under a nitrogen atmosphere, the system was heated to 80 ° C and stirred for 1 h. The system was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-100%) to obtain compound 19-10.

MS (ESI) m/z (M+H) ⁺ = 741.1.

Step 9: Preparation of compound 19-11

Compound 19-10 (270 mg, 364.49 μmol) and Molecular sieves (1 g) were dissolved in N-methylpyrrolidone (8 mL), and a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1 M, 1.09 mL) was added thereto at room temperature. After the addition, the system was heated to 130 ° C and stirred for 16 h under a nitrogen atmosphere. The system was cooled to room temperature, water (20 mL) was added thereto, and extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-100%) to obtain compound 19-11.

MS (ESI) m/z (M+H) ⁺ = 694.1.

Step 10: Preparation of compound 19-12

Compound 19-11 (60 mg, 86.49 μmol) was dissolved in anhydrous dichloromethane (2 mL), and boron tribromide (108.33 mg, 432.43 μmol, 41.67 μL) was added thereto at 0°C. After the addition, the system was heated to room temperature (25°C) and stirred for 2 h under a nitrogen atmosphere. Methanol (5 mL) was added to the system and stirred for 10 min. The system was concentrated and lyophilized to obtain compound 19-12 (hydrobromide), which was used directly in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 580.1.

Step 11: Preparation of compounds 19A and 19B

Compound 19-12 (70 mg, 120.77 μmol, hydrobromide) was dissolved in tetrahydrofuran (2 mL) and saturated sodium bicarbonate aqueous solution (6.05 g, 71.99 mmol, 2.80 mL). Acrylic anhydride (15.23 mg, 120.77 μmol) was added thereto at room temperature (25 ° C). After the addition, the system was stirred at room temperature (25 ° C) for 30 min. Methanol (2 mL) and an aqueous solution of saturated potassium carbonate aqueous solution (2 mL) were added to the system, and stirring was continued at room temperature (25 ° C) for 1 h. Water (10 mL) was added to the system to dilute it, and it was extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (methanol/dichloromethane (v/v) = 0-10%) and high performance preparative liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [water (0.05% ammonia solution)-acetonitrile]; acetonitrile%: 42%-72% 7min) to obtain compounds 19A and 19B.

Compound 19A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ9.06 (s, 1H), 7.55 (br d, J = 8.4Hz, 1H), 7.29-7.15 (m, 1H), 6.82 (dd, J = 10.4, 16.8Hz,1H),6.72-6.58(m,2H),6.27(dd,J＝2.0,16.8Hz,1H),5.81(br d,J＝11.7Hz,1H),4.64-4.09(m,4H) ,3.83-3.41(m,3H),3.12(br s,1H),2.81-2.63(m,2H),1.84-1.63(m,3H),1.18-1.06(m,12H).

MS (ESI) m/z (M+H) ⁺ = 634.3.

HPLC 91% purity; retention time 3.84 min.

Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.2mL/L ammonia solution)-acetonitrile; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 0.8mL/min.

Compound 19B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ9.07 (s, 1H), 7.56 (br d, J = 8.8Hz, 1H), 7.30-7.16 (m, 1H), 6.82 (br dd, J = 10.6 ,17.0Hz,1H),6.72-6.59(m,2H),6.27(dd,J＝1.8,16.5Hz,1H),5.82(br d,J＝10.1Hz,1H),4.67-4.09(m,4H ),3.82-3.42(m,3H),3.13(br s,1H),2.82-2.63(m,2H),1.82-1.62(m,3H),1.17-1.04(m,12H).

MS (ESI) m/z (M+H) ⁺ = 634.3.

HPLC 91% purity; retention time 3.88 min.

Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.2mL/L ammonia solution)-acetonitrile; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 0.8mL/min.

Example 20: Preparation of Compound 20

Step 1: Preparation of compound 20-1

Compound 19-9 (390 mg, 713.08 μmol), 7-1 (276.30 mg, 1.07 mmol) and N,N-diisopropylethylamine (461.72 mg, 3.57 mmol, 622.27 μL) were dissolved in acetonitrile (10 mL). Under a nitrogen atmosphere, the system was heated to 80 ° C and stirred for 12 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-100%) to obtain compound 20-1.

MS (ESI) m/z (M+H) ⁺ = 769.1.

Step 2: Preparation of compound 20-2

Compound 20-1 (400 mg, 520.31 μmol) and iron powder (116.52 mg, 2.09 mmol) were dissolved in acetic acid (7 mL), and the system was heated to 80 ° C and stirred for 45 min under a nitrogen atmosphere. The system was concentrated, diluted with dichloromethane (20 mL), and filtered. The filtrate was washed with a saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 20-2, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 707.2.

Step 3: Preparation of compound 20-3

Compound 20-2 (100 mg, 141.49 μmol) and potassium carbonate (52.99 mg, 383.44 μmol) were dissolved in acetone (2 mL). At room temperature (25 ° C), iodomethane (271.12 mg, 1.91 mmol, 118.91 μL) was added thereto. After the addition, the system was heated to 40 ° C and stirred for 16 h under a nitrogen atmosphere. The system was concentrated, and dichloromethane (10 mL) and water (10 mL) were added for liquid extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 20-3, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 721.3.

Step 4: Preparation of compound 20-4

Compound 20-3 (100 mg, 138.74 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (1 M, 1 mL) was added thereto, and the reaction was stirred at 20°C for 16 h. The reaction solution was quenched with methanol (10 mL), stirred for 10 min, and concentrated under reduced pressure to obtain compound 20-4 (hydrobromide salt), which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 607.1.

Step 5: Preparation of compound 20

Compound 20-4 (100 mg, 164.84 μmol, hydrobromide) was dissolved in tetrahydrofuran (2 mL) and saturated sodium bicarbonate aqueous solution (13.85 mg, 164.84 μmol, 6.41 μL), and acrylic anhydride (20.79 mg, 164.84 μmol) was added thereto at room temperature (25°C). After the addition, the system was stirred at room temperature (25°C) for 30 min. Methanol (2 mL) and an aqueous solution of saturated potassium carbonate aqueous solution (2 mL) were added to the system, and stirring was continued at room temperature (25°C) for 1 h. Water (10 mL) was added to the system to dilute it, and it was extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile%: 50%-80% 9min) to obtain compounds 20A and 20B.

Compound 20A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ9.08 (s, 1H), 7.68 (br d,J＝9.1Hz,1H),7.29-7.20(m,1H),7.12(dd,J＝11.0,16.8Hz,1H),6.71-6.57(m,2H),6.32-6.17(m,1H) ,5.86-5.74(m,1H),4.79-4.42(m,3H),4.02-3.86(m,2H),3.42(s,3H),3.04-2.85(m,2H),2.68-2.52(m, 1H),1.74-1.62(m,3H),1.21(d,J＝6.8Hz,3H),1.17-1.07(m,9H).

MS (ESI) m/z (M+H) ⁺ = 661.1.

HPLC 95% purity; retention time 10.49 min.

Separation conditions: Chromatographic column: WELCHΜLtimate LP-C18 150*4.6mm, 5μm; Column temperature: 40°C; Mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min. Compound 20B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ9.08 (s, 1H), 7.68 (br d, J = 8.8Hz, 1H), 7.29-7.20 (m, 1H), 7.12 (dd, J = 10.7, 16.9Hz,1H),6.72-6.59(m,2H),6.32-6.17(m,1H),5.87-5.74(m,1H),4.86-4.44(m,2H),4.04-3.86(m,2H) ,3.52-3.34(m,4H),3.05-2.85(m,2H),2.67-2.54(m,1H),1.76-1.63(m,3H),1.23-1.03(m,12H).

MS (ESI) m/z (M+H) ⁺ = 661.1.

HPLC 94% purity; retention time 10.82 min.

Separation conditions: Chromatographic column: WELCHΜLtimate LP-C18 150*4.6mm, 5μm; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min.

Example 21: Preparation of Compound 21

Step 1: Preparation of compound 21-1

Compound 3-13 (500 mg, 965.47 μmol), 7-1 (374.09 mg, 1.45 mmol) and N, N-diisopropylethylamine (625.15 mg, 4.84 mmol, 842.52 μL) were dissolved in acetonitrile (10 mL). Under a nitrogen atmosphere, the system was heated to 80 ° C and stirred for 12 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-100%) to obtain compound 21-1.

MS (ESI) m/z (M+H) ⁺ = 740.2.

Step 2: Preparation of compound 21-2

Compound 21-1 (500 mg, 675.92 μmol) and iron powder (151.36 mg, 2.71 mmol) were dissolved in acetic acid (8 mL), and the system was heated to 80 ° C and stirred for 45 min under a nitrogen atmosphere. The system was concentrated, diluted with dichloromethane (20 mL), and filtered. The filtrate was washed with a saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 21-2, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 678.1.

Step 3: Preparation of compound 21-3

Compound 21-2 (120 mg, 177.07 μmol) and potassium carbonate (66.31 mg, 479.77 μmol) were dissolved in acetone (2 mL). At room temperature (25 ° C), iodomethane (339.29 mg, 2.39 mmol, 148.81 μL) was added thereto. After the addition, the system was heated to 40 ° C and stirred for 16 h under a nitrogen atmosphere. The system was concentrated, and dichloromethane (10 mL) and water (10 mL) were added for liquid extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 21-3, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 692.2.

Step 4: Preparation of compound 21-4

Compound 21-3 (100 mg, 144.56 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (181.08 mg, 722.82 μmol, 69.65 μL) was added thereto, and the reaction was stirred at 25°C for 2 h. The reaction solution was quenched with methanol (10 mL), stirred for 10 min, and concentrated under reduced pressure to obtain compound 21-4 (hydrobromide salt), which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 578.1.

Step 5: Preparation of compounds 21A and 21B

Compound 21-4 (100 mg, 151.86 μmol, hydrobromide) was dissolved in tetrahydrofuran (2 mL) and saturated sodium bicarbonate aqueous solution (4.62 g, 55.01 mmol, 2.14 mL). Acrylic anhydride (19.15 mg, 151.86 μmol) was added thereto at room temperature (25 °C). After the addition, the system was stirred at room temperature (25 °C) for 30 min. Methanol (2 mL) and potassium carbonate aqueous solution (2 mL) were added to the system, and stirring was continued at room temperature (25 °C) for 1 h. After diluting the system with water (10 mL), it was extracted with ethyl acetate (10 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile%: 38%-68% 9min) to obtain compounds 21A and 21B.

Compound 21A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.45 (d, J = 4.9 Hz, 1H), 7.68 (br d, J = 8.2 Hz, 1H), 7.31-7.20 (m, 2H), 7.12 (dd ,J＝10.7,16.9Hz,1H),6.72-6.60(m,2H),6.30-6.21(m,1H),5.84-5.74(m,1H),4.96-4.92(m,1H),4.75(br d,J＝13.0Hz,1H),4.67-4.48(m,1H),3.91(br d,J＝12.1Hz,2H),3.44(d,J＝3.7Hz,3H),3.03-2.47(m,2H),2.29-1.90(m,3H),1.75-1.62(m,3H),1.26 -1.06(m,6H).

MS (ESI) m/z (M+H) ⁺ = 632.2.

Compound 21B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.45 (d, J = 4.9 Hz, 1H), 7.67 (br d, J = 8.8 Hz, 1H), 7.30-7.20 (m, 2H), 7.12 (dd ,J＝10.8,17.0Hz,1H),6.72-6.59(m,2H),6.31-6.20(m,1H),5.85-5.75(m,1H),4.96-4.92(m,1H),4.75(br d,J＝13.0Hz,1H),4.66-4.44(m,1H),3.91(br d,J＝11.9Hz,2H),3.44(d,J＝4.0Hz,3H),3.03-2.49(m,2H),2.24-1.94(m,3H),1.75-1.63(m,3H),1.23 -1.01(m,6H).

MS (ESI) m/z (M+H) ⁺ = 632.3.

Step 6: Separation of isomers of compound 21A

The diastereoisomer compound 21A was purified by SFC (separation conditions: chromatographic column: Phenomenex-Cell μLose-2 (250 mm*30 mm, 10 μm); mobile phase: [0.1% ammonia methanol]; methanol%: 40%-40%). After concentration, compound 21A-1 and compound 21A-2 were obtained.

Compound 21A-1:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.45 (d, J = 5.0 Hz, 1H), 7.71-7.63 (m, 1H), 7.31-7.19 (m, 2H), 7.12 (dd, J = 10.7 ,16.9Hz,1H),6.72-6.57(m,2H),6.31-6.18(m,1H),5.86-5.74(m,1H),4.98-4.92( m,1H),4.80-4.45(m,2H),4.02-3.86(m,2H),3.53-3.41(m,3H),3.03-2.85(m,1H),2.64-2.48(m,1H), 2.20(s,3H),1.74-1.65(m,3H),1.10(dd,J=6.8,12.3Hz,6H).

MS (ESI) m/z (M+H) ⁺ = 632.2.

HPLC 92% purity; retention time 8.18 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min SFC 90%ee. retention time 4.707min.

Separation conditions: Chromatographic column: Cellulose 2 100*4.6 mm ID, 3 μm; Column temperature: 35° C.; Mobile phase: CO ₂ -methanol (0.05% DEA); Methanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL/min.

Compound 21A-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 5.0Hz, 1H), 7.68 (br d,J＝8.9Hz,1H),7.29-7.19(m,2H),7.12(dd,J＝10.7,17.0Hz,1H),6.72-6.60(m,2H),6.31-6.19(m,1H) ,5.87-5.75(m,1H),4.99-4.94(m,1H),4.80-4.30(m,2H),4.01-3.84(m,2H),3.44(s,3H),3.04-2.88(m, 2H),1.99(s,3H),1.72-1.65(m,3H),1.23(d,J＝6.8Hz,3H),1.14(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 632.2.

HPLC 98% purity; retention time 8.17 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min SFC 100%ee. Retention time 5.145min.

Separation conditions: Chromatographic column: Cellulose 2 100*4.6 mm ID, 3 μm; Column temperature: 35° C.; Mobile phase: CO ₂ -methanol (0.05% DEA); Methanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL/min.

Step 7: Separation of isomers of compound 21B

The diastereoisomer compound 21B was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: [0.1% ammonia ethanol]; ethanol%: 35%-35%). After concentration, compound 21B-1 and compound 21B-2 were obtained.

Compound 21B-1:

¹ H NMR (400MHz, Methanol-d ₄ )δ8.44(d,J＝5.0Hz,1H),7.73-7.59(m,1H),7.29-7.19(m,2H),7.12(dd,J＝10.7,16.8Hz,1H),6.72-6.56(m,2H),6.32-6.17(m,1H),5.87-5.73(m,1H ),4.98-4.93(m,1H),4.80-4.38(m,2H),4.00-3.85(m,2H),3.52-3.40(m,3H),3.03-2.87(m,2H),1.98(s,3H),1.75-1.63(m,3H),1.19(dd,J＝6.7 ,20.0Hz,6H).

MS (ESI) m/z (M+H) ⁺ = 632.1.

HPLC 99% purity; retention time 8.38 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min SFC 100%ee. Retention time 4.041min.

Separation conditions: Chromatographic column: Chiralpak AD-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% for 5 min, 40% for 2.5 min, 5% for 2.5 min; flow rate: 2.5 mL/min.

Compound 21B-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.45 (d, J = 5.0 Hz, 1H), 7.71-7.63 (m, 1H), 7.31-7.20 (m, 2H), 7.12 (dd, J = 10.7 ,16.9Hz,1H),6.73-6.59(m,2H),6.30-6.19(m,1H),5.86-5.72(m,1H),4.98-4.92( m,1H),4.80-4.36(m,2H),4.02-3.85(m,2H),3.54-3.41(m,3H),3.02-2.85(m,1H),2.54(td,J＝6.6,13.4 Hz,1H),2.20(s,3H),1.75-1.64(m,3H),1.16-1.00(m,6H).

MS (ESI) m/z (M+H) ⁺ = 632.1.

HPLC 99% purity; retention time 8.30 min.

Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40°C; Mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min SFC 100% ee. Retention time 4.707min

Separation conditions: Chromatographic column: Chiralpak AD-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% for 5 min, 40% for 2.5 min, 5% for 2.5 min; flow rate: 2.5 mL/min.

Example 22: Preparation of Compound 22

Step 1: Preparation of compound 22-1

Compound 21-2 (80 mg, 118.04 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (147.86 mg, 590.22 μmol, 56.87 μL) was added thereto, and the reaction was stirred at 25°C for 2 h. The reaction solution was quenched with methanol (10 mL), stirred for 10 min, and concentrated under reduced pressure to obtain compound 22-1 (hydrobromide salt), which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 564.1.

Step 2: Preparation of compounds 22A and 22B

Compound 22-1 (80 mg, 124.13 μmol, hydrobromide) was dissolved in tetrahydrofuran (2 mL) and saturated sodium bicarbonate aqueous solution (3.78 g, 44.97 mmol, 1.75 mL). Acrylic anhydride (15.65 mg, 124.13 μmol) was added at room temperature (25 ° C). After the addition, the system was stirred at room temperature (25 ° C) for 30 min. Methanol (2 mL) and potassium carbonate aqueous solution (2 mL) were added to the system, and stirring was continued at room temperature (25 ° C) for 1 h. After diluting the system with water (10 mL), it was extracted with ethyl acetate (10 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile%: 37%-67% 9min) to obtain compounds 22A and 22B.

Compound 22A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 5.1 Hz, 1H), 7.63 (br d, J = 9.0 Hz, 1H), 7.32-7.17 (m, 2H), 7.09 (br dd,J＝10.7,17.1Hz,1H),6.74-6.57(m,2H),6.29-6.18(m,1H),5.84-5.75(m,1H),4.82-4.46(m,3H),4.13- 3.72(m,2H),3.17-2.97(m,1H),2.80-2.67(m,1H),2.09-2.02(m,3H),1.76-1.58(m,3H),1.20-1.05(m,6H ).

MS (ESI) m/z (M+H) ⁺ = 618.2.

Compound 22B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 5.1 Hz, 1H), 7.63 (br d, J = 9.0 Hz, 1H), 7.31-7.21 (m, 2H), 7.10 (dd ,J＝10.8,16.8Hz,1H),6.73-6.59(m,2H),6.31-6.18(m,1H),5.88-5.72(m,1H),5.01-4.93(m,1H),4.80(br d,J＝13.9Hz,1H),4.71-4.39(m,1H),4.11-3.77(m,2H),3.03(br t,J＝9.0Hz,1H),2.73(td,J＝6.9,10.1Hz,1H),2.07(d,J＝13.0Hz,3H),1.74-1.60(m,3H),1.19-1.05(m ,6H).

MS(ESI)m/z(M+H) ⁺ =618.2&618.1.

Step 3: Separation of isomers of compound 22A

The diastereoisomer compound 21A was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: [Neu-ethanol]; ethanol%: 50%-50%). After concentration, compound 22A-1 and compound 22A-2 were obtained.

Compound 22A-1:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 5.1 Hz, 1H), 7.63 (br d, J = 9.0 Hz, 1H), 7.30-7.20 (m, 2H), 7.09 (dd ,J＝10.8,17.0Hz,1H),6.73-6.60(m,2H),6.31-6.18(m,1H),5.87-5.72(m,1H),4.93(br s,1H),4.83-4.75(m,1H),4.66-4.46(m,1H),4.08-3.83(m,2H),3.17-3.00(m,1H),2.83-2.68(m,1H), 2.07(s,3H),1.74-1.63(m,3H),1.18(d,J＝6.8Hz,3H),1.09(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 618.1.

HPLC 100% purity; retention time 7.85 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-Acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min. SFC 100% ee. Retention time 4.917min.

Separation conditions: Chromatographic column: Chiralcel OD-3 100*4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% 4min, 40% 2.5min, 5% 1.5min; flow rate: 2.8mL/min.

Compound 22A-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 5.1 Hz, 1H), 7.73-7.57 (m, 1H), 7.33-7.19 (m, 2H), 7.10 (dd, J = 10.7 ,17.1Hz,1H),6.71-6.57(m,2H),6.32-6.17(m,1H),5.88-5.73(m,1H),4.99(br s,1H),4.83-4.50(m,2H),4.10-3.84(m,2H),3.14-2.98(m,1H),2.78-2.67(m,1H),2.09(s,3H),1.76- 1.63(m,3H),1.14(dd,J=6.8,9.9Hz,6H).

MS (ESI) m/z (M+H) ⁺ = 618.1.

HPLC 99.3% purity; retention time 7.91 min.

Separation conditions: Chromatographic column: WELCHΜLtimate LP-C18 150*4.6mm 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min SFC 98.5%ee. Retention time 5.310min.

Separation conditions: Chromatographic column: Chiralcel OD-3 100*4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% 4min, 40% 2.5min, 5% 1.5min; flow rate: 2.8mL/min.

Step 4: Separation of isomers of compound 22B

The diastereoisomer compound 21A was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: [Neu-methanol]; methanol%: 40%-40%). After concentration, compound 22B-1 and compound 22B-2 were obtained.

Compound 22B-1:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 5.1 Hz, 1H), 7.63 (br d, J = 9.0 Hz, 1H), 7.28-7.18 (m, 2H), 7.09 (dd ,J＝10.7,17.1Hz,1H),6.70-6.61(m,2H),6.29-6.17(m,1H),5.83-5.74(m,1H),4.97-4.92(m,1H),4.78(br s,1H),4.64-4.48(m,1H),4.06-3.85(m,2H),3.14-2.98(m,1H),2.81-2.64(m,1H),2.06(s,3H),1.74- 1.65(m,3H),1.15(dd,J=6.8,18.3Hz,6H).

MS (ESI) m/z (M+H) ⁺ = 618.1.

HPLC 93.6% purity; retention time 8.14 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-Acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min. SFC 100% ee. Retention time 3.589min.

Separation conditions: Chromatographic column: Chiralcel OD-3 100*4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO ₂ -methanol (0.05% DEA); methanol: 40%-40%; flow rate: 2.8mL/min.

Compound 22B-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 5.1 Hz, 1H), 7.63 (br d, J = 8.8 Hz, 1H), 7.28-7.19 (m, 2H), 7.09 (dd ,J＝10.7,17.1Hz,1H),6.72-6.58(m,2H),6.29-6.18(m,1H),5.83-5.73(m,1H),4.99-4.91(m,1H),4.78(br s,1H),4.67-4.42(m,1H),4.09-3.86(m,2H),3.14-2.97(m,1H),2.80-2.62(m,1H),2.19-2.05(m,3H), 1.75-1.64(m,3H),1.16(brd,J＝6.8Hz,3H),1.08(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 618.1.

HPLC 99.3% purity; retention time 8.12 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min SFC 97.8%ee. Retention time 4.079min.

Separation conditions: Chromatographic column: Chiralcel OD-3 100*4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO ₂ -methanol (0.05% DEA); methanol: 40%-40%; flow rate: 2.8mL/min.

Example 23: Preparation of Compound 23

Step 1: Preparation of compound 23-1

Under nitrogen protection, compound 18-6 (450 mg, 842.16 μmol) was dissolved in acetonitrile (8 mL), and diisopropylethylamine (545.29 mg, 4.22 mmol, 734.90 μL) and compound JMKX-1805-Inter 5A (326.31 mg, 1.26 mmol) were added in sequence, and the reaction temperature was raised to 80 ° C and stirred for 12 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/0 to 0/1) to obtain compound 23-1.

MS (ESI) m/z (M+H) ⁺ = 756.2.

Step 2: Preparation of compound 23-2

Compound 23-1 (200 mg, 264.48 μmol) and iron powder (59.23 mg, 1.06 mmol) were dissolved in acetic acid (5 mL), and the system was heated to 80 ° C and stirred for 45 min under a nitrogen atmosphere. The system was concentrated, diluted with dichloromethane (20 mL), and filtered. The filtrate was washed with a saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 23-2, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 694.1.

Step 3: Preparation of compound 23-3

Compound 23-2 (150 mg, 216.09 μmol) and potassium carbonate (80.94 mg, 585.60 μmol) were dissolved in acetone (2 mL). At room temperature (25 ° C), iodomethane (414.06 mg, 2.92 mmol, 181.61 μL) was added thereto. After the addition, the system was heated to 40 ° C and stirred for 16 h under a nitrogen atmosphere. The system was concentrated, and dichloromethane (10 mL) and water (10 mL) were added for liquid extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 23-3, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 708.1.

Step 4: Preparation of compound 23-4

Compound 23-3 (110 mg, 155.33 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (1 M, 776.63 μL) was added thereto, and the reaction was stirred at 20°C for 2 h. The reaction solution was quenched with methanol (5 mL), stirred for 10 min, and concentrated under reduced pressure to obtain compound 23-4 (hydrobromide salt), which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 594.1.

Step 5: Preparation of compounds 23A and 23B

Compound 23-4 (130 mg, 153.92 μmol, hydrobromide) was dissolved in tetrahydrofuran (5 mL) and saturated sodium bicarbonate aqueous solution (4.32 g, 51.42 mmol, 2 mL), and acrylic anhydride (19.41 mg, 153.92 μmol) was added thereto at room temperature (25 ° C). After the addition, the system was stirred at room temperature (25 ° C) for 30 min. Methanol (2 mL) and an aqueous solution of saturated potassium carbonate aqueous solution (2 mL) were added to the system, and stirring was continued at room temperature (25 ° C) for 1 h. Water (10 mL) was added to the system to dilute it, and it was extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile%: 44%-74% 9min) to obtain compounds 23A and 23B.

Compound 23A:

¹ H NMR (400MHz, Methanol-d ₄ )δ8.44(d,J＝4.8Hz,1H),8.02(s,1H),7.30-7.07(m,3H),6.72-6.57(m,2H),6.32-6.19(m,1H),5.86-5.75(m,1H),4.98-4.94(m,1H),4.80-4.48(m ,2H),4.01-3.84(m,2H),3.44(d,J=3.8Hz,3H),3.02-2.89(m,1H),2.62-2.47(m,1H),2.22-1.97(m,3H),1.77-1.62(m,3H),1.25-1.04(m,6H).MS(ES) I)m/z(M+H) ⁺ =648.1.

Compound 23B:

¹ H NMR (400MHz, Methanol-d ₄ )δ8.44(d,J＝5.0Hz,1H),8.02(s,1H),7.31-7.06(m,3H),6.74-6.57(m,2H),6.30-6.20(m,1H),5.86-5.76(m,1H),4.98-4.94(m,1H),4.76(brd,J＝1 3.3Hz,2H),4.03-3.87(m,2H),3.44(d,J＝3.8Hz,3H),3.00-2.88(m,1H),2.59-2.49(m,1H),2.25-1.93(m,3H),1.75-1.64(m,3H),1.24-1.00(m,6H). MS(ESI)m/z(M+H) ⁺ =648.1.

Step 6: Separation of isomers of compound 23A

The diastereoisomer compound 23A was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALCEL OJH (250mm*30mm, 5μm); mobile phase: [0.1% ammonia isopropanol]; isopropanol%: 35%-35%). After concentration, compound 23A-1 (2.46mg, yield 12.30%) and 23A-2 (4.07mg, yield 20.35%) were obtained.

Compound 23A-1:

¹ H NMR (400MHz, Acetonitrile-d ₃ ) δ8.45 (d, J = 4.9 Hz, 1H), 8.01-7.96 (m, 1H), 7.28 (dt, J = 6.9, 8.3 Hz, 1H), 7.18 ( d,J＝4.9Hz,1H),7.02(dd,J＝10.6,16.9Hz,1H),6.77-6.69(m,2H),6.26-6.15(m,1H),5.79-5.67(m,1H) ,4.89(br s,1H),4.69-4.31(m,1H),3.90-3.74(m,2H),3.39(s,3H),3.20(br d,J＝12.3Hz,1H),3.01-2.80(m,1H),2.59(td,J＝6.6,13.3Hz,1H),2.14(s,3H),1.67-1.58(m,3H),1.06 (d,J＝6.7Hz,3H),1.01(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 648.2.

SFC retention time 2.544 min

Separation conditions: Chromatographic column: Chiralcel OJ-3 100 mm x 4.6 mm ID, 3 μm; Column temperature: 35° C.; Mobile phase: CO ₂ -ethanol (0.05% DEA); Ethanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL/min.

Compound 23A-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.48 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 1.4 Hz, 1H), 7.37 (br d, J = 5.1 Hz, 1H), 7.23(dt,J＝6.8,8.3Hz,1H),7.11(dd,J＝10.8,17.0Hz,1H),6.73-6.59(m,2H),6.31-6.18(m,1H),5.86-5.73( m,1H),4.99-4.93(m,1H),4.75(br d,J＝13.0Hz,2H),3.98-3.84(m,2H),3.43(s,3H),3.14-2.86(m,2H),2.04(s,3H),1.76-1.63(m,3H) ,1.25(d,J＝6.8Hz,3H),1.15(d,J＝6.8Hz,3H).MS(ESI)m/z(M+H) ⁺ =648.2.

SFC retention time: 2.670 min.

Separation conditions: Chromatographic column: Chiralcel OJ-3 100 mm x 4.6 mm ID, 3 μm; Column temperature: 35° C.; Mobile phase: CO ₂ -ethanol (0.05% DEA); Ethanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL/min.

Step 7: Separation of isomers of compound 23B

The diastereoisomer compound 23B was purified by SFC (separation conditions: chromatographic column: REGIS (s, s) WHELK-O1 (250 mm*30 mm, 5 μm); mobile phase: [0.1% ammonia ethanol]; ethanol%: 40%-40%). After concentration, compound 23B-1 and compound 23B-2 were obtained.

Compound 23B-1:

¹ H NMR (400MHz, Acetonitrile-d ₃ ) δ8.43 (d, J = 4.9 Hz, 1H), 8.00-7.93 (m, 1H), 7.31-7.22 (m, 1H), 7.12 (d, J = 4.9 Hz,1H),7.01(dd,J＝10.6,16.9Hz,1H),6.77-6.66(m,2H),6.25-6.13(m,1H),5.78-5.65(m,1H),4.87(br s,1H),4.67-4.31(m,1H),3.83-3.66(m,2H),3.40-3.32(m,3H),3.21(d,J＝11.2Hz,1H),3.01-2.81(m, 2H),2.10(br s,3H),1.66-1.54(m,3H),1.12(d,J＝6.7Hz,3H),1.07(d,J＝6.7Hz,3H).MS(ESI)m/ z(M+H) ⁺ =648.2.

SFC retention time 5.051 min

Separation conditions: Chromatographic column: (S,S)-Whelk-O1 100mm x 4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% 4min, 40% 2.5min, 5% 1.5min; flow rate: 2.8mL/min.

Compound 23B-2:

¹ H NMR (400MHz, Acetonitrile-d ₃ ) δ8.46 (d, J = 4.9 Hz, 1H), 8.02-7.95 (m, 1H), 7.34-7.24 (m, 1H), 7.20 (d, J = 4.9 Hz,1H),7.02(dd,J＝10.6,16.8Hz,1H),6.78(d,J＝8.3Hz,1H),6.75-6.66(m,1H),6.27-6.14(m,1H),5.79 -5.67(m,1H),4.89(br s,1H),4.65(d,J＝13.6Hz,1H),3.90-3.74(m,2H),3.44-3.34(m,3H),3.20(br d,J＝12.2Hz,1H),3.04-2.80(m,1H),2.57(td,J＝6.6,13.3Hz,1H),2.16(s,3H),1.68-1.58(m,3H),1.06 (d,J＝6.7Hz,3H),0.97(d,J＝6.7Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 648.2.

SFC retention time 5.618 min

Separation conditions: Chromatographic column: (S,S)-Whelk-O1 100mm x 4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% 4min, 40% 2.5min, 5% 1.5min; flow rate: 2.8mL/min.

Example 24: Preparation of Compound 24

Step 1: Preparation of compound 24-1

Compound 21-2 (100 mg, 147.56 μmol) and potassium carbonate (123 mg, 889.98 μmol) were dissolved in N, N-dimethylformamide (3 mL). 2-Bromo-N, N-dimethylethylamine (100 mg, 429.29 μmol, HBr) and potassium iodide (25 mg, 150.60 μmol) were added at room temperature (25 ° C). After the addition, the system was heated to 100 ° C and stirred for 16 hours. The system was diluted with ethyl acetate (30 mL), washed with water (20 mL) and saturated brine (20 mL) in turn, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1/15) to obtain compound 24-1.

MS (ESI) m/z (M+H) ⁺ = 749.4.

Step 2: Preparation of compound 24-2

Compound 24-1 (45 mg, 60.09 μmol) was dissolved in dichloromethane (0.5 mL), and boron tribromide (1 M, 1 mL) was added thereto. The reaction was stirred at room temperature (20°C) for 8 h under a nitrogen atmosphere. The reaction solution was quenched with methanol (5 mL), stirred for 10 min, and concentrated under reduced pressure to obtain compound 24-2 (hydrobromide salt), which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 635.2.

Step 3: Preparation of compounds 24A, 24B, 24C and 24D

Compound 24-2 (45 mg, 62.88 μmol, hydrobromide) was dissolved in tetrahydrofuran (2 mL) and saturated sodium bicarbonate aqueous solution (2.16 g, 25.71 mmol, 1 mL). A solution of acrylic anhydride (15 mg, 118.94 μmol) in tetrahydrofuran (0.5 mL) was added at room temperature (25 ° C). After the addition, the system was stirred at room temperature (25 ° C) for 2 h. Methanol (1 mL) and saturated potassium carbonate aqueous solution (2M, 1 mL) were added to the system, and stirring was continued at room temperature (25 ° C) for 1.5 h. Water (10 mL) was added to the system for dilution, pH was adjusted to 7 with 1N HCl, and extracted with ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid phase (separation conditions: chromatographic column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile%: 40%-70% 9min) and then purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALCEL OD (250mm*30mm, 10μm); mobile phase: [0.1% ammonia isopropanol]; isopropanol%: 25%-25% and DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: [0.1% ammonia ethanol]; ethanol%: 25%-25%). After concentration, compounds 24A, 24B, 24C and 24D were obtained.

Compound 24A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.46 (d, J = 5.0 Hz, 1H), 7.74-7.63 (m, 1H), 7.32-7.21 (m, 2H), 7.11 (dd, J = 10.8 ,16.8Hz,1H),6.74-6.59(m,2H),6.24(d,J＝15.1Hz,1H),5.81(br d,J＝10.8Hz,1H),5.01-4.94(m,1H), 4.75(d,J＝12.5Hz,1H),4.64-4.46(m,1H),4.40-4.24(m,1H),4.13(br s,1H),4.05-3.88(m,2H),3.37(s,2H),3.03(br d,J＝14.6Hz,1H),2.83-2.49(m,7H),2.21(s,3H), 1.78-1.67(m,3H),1.13(d,J＝6.8Hz,3H),1.03(d,J＝6.5Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 689.2.

SFC retention time: 3.949 min.

Separation conditions: Chromatographic column: Chiralpak AD-3 150 mm x 4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); ethanol: 5%-40% 5 min, 40%-5% 0.5 min, 5% 1.5 min; flow rate: 2.5 mL/min.

Compound 24B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.35 (d, J = 5.1 Hz, 1H), 7.59 (br d, J = 9.3 Hz, 1H), 7.21-7.10 (m, 2H), 7.03 (dd ,J＝10.8,17.0Hz,1H),6.60-6.47(m,2H),6.21-6.06(m,1H),5.71(br d,J＝11.0Hz,1H),4.88-4.85(m,1H) ,4.65(br d,J＝13.9Hz,1H),4.51(s,1H),4.22(br dd,J＝7.8,15.8Hz,2H),3.90-3.75(m,2H),3.04(br d,J＝8.8Hz,1H),2.63-2.35(m,3H),2.20-2.06(m,9H),1.65-1.56(m,3H),1.00(dd,J＝6.8,15.0Hz,6H) .

MS (ESI) m/z (M+H) ⁺ = 689.4.

SFC retention time: 3.389 min.

Separation conditions: Chromatographic column: Chiralpak AD-3 150 mm x 4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); ethanol: 5%-40% 5 min, 40%-5% 0.5 min, 5% 1.5 min; flow rate: 2.5 mL/min.

Compound 24C:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.45 (d, J = 5.0 Hz, 1H), 7.70 (br d, J = 9.3 Hz, 1H), 7.30-7.21 (m, 2H), 7.13 (dd ,J＝10.7,16.9Hz,1H),6.75-6.60(m,2H),6.23(d,J＝15.1Hz,1H),5.81(br d,J＝12.3Hz,1H),4.95(br s, 1H),4.74(br d,J＝12.5Hz,1H),4.61(s,1H),4.30(br d,J＝6.8Hz,2H),4.00-3.85(m,2H),3.24-3.12(m,1H),3.01-2.89(m,1H),2.71(br s,1H),2.60(br s, 1H),2.40-2.24(m,6H),1.99(s,3H),1.74-1.66(m,3H),1.24(d,J＝6.8Hz,3H),1.13(d,J＝6.5Hz,3H ).

MS (ESI) m/z (M+H) ⁺ = 689.4.

SFC retention time: 3.917 min.

Separation conditions: Chromatographic column: Chiralpak AD-3 150 mm x 4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); ethanol: 5%-40% 5 min, 40%-5% 0.5 min, 5% 1.5 min; flow rate: 2.5 mL/min.

Compound 24D:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.43 (d, J = 4.9 Hz, 1H), 7.68 (br d, J = 7.7 Hz, 1H), 7.29-7.17 (m, 2H), 7.11 (br dd,J＝10.5,16.9Hz,1H),6.71-6.58(m,2H),6.28-6.14(m,1H),5.79(br d,J＝10.8Hz,1H),4.97-4.93(m,1H ),4.72(br d,J＝12.3Hz,1H),4.59(s,1H),4.28(br t,J＝6.5Hz,2H),4.01-3.84(m,2H),3.21

-3.08(m,1H),2.98-2.87(m,1H),2.64(br s,1H),2.52(br s,1H),2.35-2.14(m,6H),1.96(s,3H),1.72 -1.62(m,3H),1.21(br d,J＝6.8Hz,3H),1.14(br d,J＝6.6Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 689.4.

SFC retention time 4.278 min.

Separation conditions: Chromatographic column: Chiralpak AD-3 150 mm x 4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); ethanol: 5%-40% 5 min, 40%-5% 0.5 min, 5% 1.5 min; flow rate: 2.5 mL/min.

Example 25: Preparation of Compounds 25A and 25B

Step 1: Preparation of compound 25-1

Compound 8-9 (426 mg, 1.0 mmol), 7-1 (286 mg, 1.1 mmol), N,N-diisopropylethylamine (0.2 mL) were dissolved in acetonitrile (10 mL), and the system was heated to 100 ° C and stirred for 4 hours. The system was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-35%) to obtain compound 25-1.

MS (ESI) m/z (M+H) ⁺ = 649.0.

Step 2: Preparation of compound 25-2

Compound 25-1 (326 mg, 0.502 mmol) and iron powder (200 mg, 3.6 mmol) were dissolved in acetic acid (15 mL). Under nitrogen atmosphere, the system was heated to 85 ° C and stirred for 1 h. The system was filtered through diatomaceous earth, the filtrate was concentrated, the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 25-2. It was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 587.0.

Step 3: Preparation of compound 25-3

Compound 25-2 (277 mg, 0.5 mmol), compound 2-3 (282 mg, 1 mmol), tetrakis(triphenylphosphine)palladium (150 mg, 0.125 mmol), potassium carbonate (138 mg, 1 mmol) were dissolved in a mixed solution of dioxane (18 mL) and water (1.8 mL). Under a nitrogen atmosphere, the system was heated to 100 ° C and stirred for 2 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 25-3.

MS (ESI) m/z (M+H) ⁺ = 707.2.

Step 4: Preparation of compound 25-4

Compound 25-3 (40 mg, 0.057 mmol) and potassium carbonate (21 mg, 0.15 mmol) were dissolved in acetone (3 mL). At room temperature (20 ° C), methyl iodide (21 mg, 0.15 mmol) was added. After the addition, the system was heated to 60 ° C and stirred for 3 h under a nitrogen atmosphere. The system was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 25-4.

MS (ESI) m/z (M+H) ⁺ = 721.2.

Step 5: Preparation of compound 25-5

Compound 25-4 (50 mg, 0.069 mmol) and hydrochloric acid (6N, 2 mL) were added to a mixed solution of methanol (2 mL) and tetrahydrofuran (0.2 mL). The system was heated to 55°C and reacted for 10 min. The system was concentrated to obtain a crude compound 25-5, which was used directly in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 577.2.

Step 6: Preparation of compound 25

Compound 25-5 (40 mg, 0.069 mmol) was dissolved in dichloromethane (5 mL), the system was cooled to 0°C, triethylamine (39 mg, 0.39 mmol) and acryloyl chloride (23 mg, 0.26 mmol) were added dropwise, and the system was reacted at 0°C for 0.5 h. The system was quenched with methanol and concentrated to obtain a crude product. The crude product was dissolved in methanol (5 mL), potassium carbonate (140 mg) was added thereto, and after the addition was completed, the system was stirred at room temperature (20°C) for 30 min. The system was adjusted to pH ~ 6 with hydrochloric acid, and extracted with dichloromethane (10 mL) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column 5μm F5 LC Column 150x21.2mm, mobile phase: water (0.1% FA)-acetonitrile; acetonitrile 22%-42% 9min; flow rate 30mL/min) to obtain compound 25.

MS (ESI) m/z (M+H) ⁺ = 631.2.

Step 7: Preparation of compounds 25A and 25B

The diastereoisomer compound 25 was purified by SFC (ChiralPak AD, 250×30 mm ID, 10 μm; mobile phase: [CO ₂ -ethanol (0.1% ammonia water)]; ethanol%: 35%; flow rate: 80 mL/min; column temperature: 38° C.) After concentration, compound 25A and compound 25B were obtained.

Compound 25A

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.07 (s, 1H), 8.44 (d, J = 4.9Hz, 1H), 8.24 (s, 1H), 7.30–7.17 (m, 2H), 7.03 ( dd,J＝16.8,10.6Hz,1H),6.76–6.63(m,2H),6.15(dd,J＝16.8,2.5Hz,1H),5.77(dd,J＝10.6,2.5Hz,1H),4.85 –4.72(m,1H),4.62(d,J＝14.0Hz ,1H),3.99–3.91(m,1H),3.76(dd,J＝14.1,4.3Hz,1H),3.51–3.39(m,1H),2.91–2.83(m,1H),2.76(p,J ＝6.8Hz,1H),1.81(d,J＝9.0Hz,3H),1.53(d,J＝6.8Hz,3H),1.24(s,3H),1.11(d,J＝6.6Hz,3H), 0.96(d,J＝6.6Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 631.2.

SFC 100% ee. Retention time 4.102 min.

Separation conditions: Chromatographic column: ChiralPak AD-3, 150×4.6 mm ID, 3 μm; Mobile phase: [CO ₂ -ethanol (0.05% DEA)]; Ethanol%: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35°C

Compound 25B

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.98 (d, J = 14.4Hz, 1H), 8.36 (d, J = 4.8Hz, 1H), 8.17 (s, 1H), 7.16 (d, J = 8.5Hz,2H),6.96(dd,J＝16.9,10.6Hz,1H),6.69–6.54(m,2H),6.08(dd,J＝16.8,2.4Hz,1H),5.69(dd,J＝10.5 ,2.4Hz,1H),4.74–4.63(m,1H),4.54(d, J＝14.1Hz,1H),4.05–3.87(m,1H),3.68(dd,J＝14.1,4.3Hz,1H),3.37–3.26(m,1H),2.93–2.79(m,1H),2.80 –2.68(m,1H),1.92(d,J＝3.2Hz,3H),1.46(d,J＝6.8Hz,3H),1.17(s,3H),0.96(d,J＝6.6Hz,3H) ,0.85–0.73(m,3H).

MS (ESI) m/z (M+H) ⁺ = 631.2.

SFC 100% ee. Retention time 5.424 min.

Separation conditions: Chromatographic column: ChiralPak AD-3, 150×4.6 mm ID, 3 μm; Mobile phase: [CO ₂ -ethanol (0.05% DEA)]; Ethanol%: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35°C

Example 26: Preparation of Compound 26

Step 1: Preparation of compound 26-2

Compound 23-2 (400 mg, 576.23 μmol) and cesium carbonate (563.24 mg, 1.73 mmol) were dissolved in N,N-dimethylformamide (5 mL), and compound 26-2 (185.98 mg, 1.73 mmol) was added thereto at room temperature (25 ° C). After the addition, the system was heated to 120 ° C and stirred for 3 h under a nitrogen atmosphere. The system was concentrated, diluted with ethyl acetate (20 mL) and filtered, and the filtrate was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1/10) to obtain compound 26-2.

MS (ESI) m/z (M+H) ⁺ = 765.5.

Step 2: Preparation of compound 26-3

Compound 26-2 (230 mg, 345.78 μmol) was dissolved in dichloromethane (1 mL), and boron tribromide (1 M, 407.10 uL) was added thereto. The reaction was stirred at 20 °C for 16 h. The reaction solution was quenched with methanol (5 mL) and stirred for 10 min. Saturated sodium bicarbonate (30 mL) was added to the system, and it was extracted with dichloromethane (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 26-3, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 651.3.

Step 3: Preparation of compounds 26A and 26B

Compound 26-3 (280 mg, 430.01 μmol) was dissolved in tetrahydrofuran (3 mL) and saturated sodium bicarbonate aqueous solution (4.32 g, 51.42 mmol, 2 mL). Acrylic anhydride (108.46 mg, 860.02 μmol) was added at room temperature (25 ° C). After the addition, the system was stirred at room temperature (25 ° C) for 30 min. Water (10 mL) was added to the system for dilution, and extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile%: 55%-85% 9min), and then purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: [CO ₂ -(0.1% ammonia water) isopropanol]; isopropanol%: 35%-35%). After concentration, compounds 26A, 26B, 26C and 26D were obtained.

Compound 26A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 5.0 Hz, 1H), 8.04 (s, 1H), 7.31-7.20 (m, 2H), 7.13 (dd, J = 10.7, 16.9 Hz,1H),6.69(d,J＝8.3Hz,1H),6.63(t,J＝8.8Hz,1H),6.30-6.19(m,1H),5.86-5.75(m,1H),4.99-4.94 (m,1H),4.75(br d,J＝13.8Hz,1H),4.67-4.44(m,1H),4.39-4.23(m,2H),4.03-3.85(m,2H),3.22-3.07(m,1H),2.66(br d ,J＝11.8Hz,1H),2.60-2.47(m,2H),2.32-2.09(m,9H),1.76-1.64(m,3H),1.12(d,J＝6.8Hz,3H),1.02( d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 705.3.

HPLC retention time: 6.9 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-Acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min. SFC retention time 4.077min

Separation conditions: Chromatographic column: Chiralpak AD-3 150x4.6mm ID, 3μm; Column temperature: 35°C; Mobile phase: CO ₂ -isopropanol (0.05% DEA); Isopropanol: 5%-40% 5min, 40% 2.5min, 5% 2.5min; Flow rate: 2.5mL/min.

Compound 26B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.52-8.34(m,1H),8.03(s,1H),7.31-7.19(m,2H),7.13(dd,J＝10.8,16.8Hz,1H ),6.72-6.56(m,2H),6.32-6.16(m,1H),5.89-5.73(m,1H),4.95(br s,1H),4.81-4.68(m,1H),4.67-4.44(m,1H),4.39-4.20(m,2H),4.04-3.84(m,2H),3.14(dd,J＝3.5,12.0 Hz,1H),2.72-2.42(m,3H),2.31-2.18(m,9H),1.76-1.64(m,3H),1.10(dd,J=6.8,15.1Hz,6H).

MS (ESI) m/z (M+H) ⁺ = 705.3.

HPLC retention time: 6.67 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40°C; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-Acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min SFC retention time 4.515min

Separation conditions: Chromatographic column: Chiralpak AD-3 150x4.6mm ID, 3μm; Column temperature: 35°C; Mobile phase: CO ₂ -isopropanol (0.05% DEA); Isopropanol: 5%-40% 5min, 40% 2.5min, 5% 2.5min; Flow rate: 2.5mL/min.

Compound 26C:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 5.0 Hz, 1H), 8.04 (s, 1H), 7.30-7.20 (m, 2H), 7.13 (dd, J = 10.7, 16.9 Hz,1H),6.73-6.58(m,2H),6.32-6.16(m,1H),5.87-5.73(m,1H),4.95(br s,1H),4.74(br d,J＝13.6Hz, 1H),4.66-4.45(m,1H),4.37-4.20(m,2H),3.99-3.82(m,2H),3.20(br dd,J＝3.4,12.4Hz,1H),2.94(td,J＝6.7,13.5Hz,1H),2.67(br d,J＝12.0Hz,1H),2.55(br d,J＝5.3Hz,1H ),2.34-2.15(m,6H),2.10-1.93(m,3H),1.77-1.61(m,3H),1.23(d,J＝6.8Hz,3H),1.11(d,J＝6.8Hz, 3H).

MS (ESI) m/z (M+H) ⁺ = 705.3.

HPLC retention time: 6.67 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40°C; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-Acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min SFC retention time 4.826min

Separation conditions: Chromatographic column: Chiralpak AD-3 150x4.6mm ID, 3μm; Column temperature: 35°C; Mobile phase: CO ₂ -isopropanol (0.05% DEA); Isopropanol: 5%-40% 5min, 40% 2.5min, 5% 2.5min; Flow rate: 2.5mL/min.

Compound 26D:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 4.8 Hz, 1H), 8.04 (s, 1H), 7.34-7.20 (m, 2H), 7.13 (dd, J = 10.7, 16.9 Hz,1H),6.72-6.53(m,2H),6.33-6.15(m,1H),5.92-5.65(m,1H),4.95(br s,1H),4.75(d,J＝12.8Hz,1H ),4.66-4.42(m,1H),4.30(br t,J＝6.9Hz,2H),4.02-3.83(m,2H),3.26-3.13(m,1H),2.93(quin,J＝6.8Hz,1H),2.74-2.59(m,1H),2.58 -2.45(m,1H),2.34-2.18(m,6H),1.99(s,3H),1.78-1.63(m,3H),1.22(d,J＝6.8Hz,3H),1.15(d,J =6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 705.3.

HPLC retention time: 6.88 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40°C; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-Acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min SFC retention time 5.114min

Separation conditions: Chromatographic column: Chiralpak AD-3 150x4.6mm ID, 3μm; Column temperature: 35°C; Mobile phase: CO ₂ -isopropanol (0.05% DEA); Isopropanol: 5%-40% 5min, 40% 2.5min, 5% 2.5min; Flow rate: 2.5mL/min.

Example 27: Preparation of Compound 27

Step 1: Preparation of compound 27-1

Compound 26-2 (600 mg, 784.02 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.83 g, 16.06 mmol, 1.19 mL) was added, and the mixture was stirred at 25° C. for 16 h. The reaction solution was concentrated to obtain compound 27-1, which was used directly in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 665.3.

Step 2: Preparation of compound 27

Compound 27-1 (200 mg, 300.67 μmol) was dissolved in tetrahydrofuran (2 mL) and saturated sodium bicarbonate aqueous solution (4.32 g, 51.42 mmol, 2 mL). Acrylic anhydride (75.84 mg, 601.35 μmol) was added at room temperature (25 ° C). After the addition, the system was stirred at room temperature (25 ° C) for 30 min. Water (10 mL) was added to the system for dilution, and extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile%: 49%-79% 9min), and then purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: [CO ₂ -(0.1% ammonia water) ethanol]; ethanol%: 25%-25%). After concentration, compounds 27A, 27B, 27C and 27D were obtained.

Compound 27A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 5.0Hz, 1H), 8.03 (d, J = 1.3Hz, 1H), 7.46-7.38 (m, 1H), 7.27 (d, J＝5.0Hz,1H),7.13(dd,J＝10.8,16.8Hz,1H),6.89(d,J＝8.5Hz,1H),6.79(t,J＝8.8Hz,1H),6.31-6.18( m,1H),5.87-5.75(m,1H),4.95(br s,1H),4.80-4.70(m,1H),4.68-4.42(m,1H),4.39-4.26(m,2H),4.02-3.87(m,2H),3.68(s,3H),3.25- 3.12(m,1H),2.65-2.37(m,3H),2.23-2.14(m,9H),1.76-1.64(m,3H),1.13(d,J＝6.8Hz,3H),1.05(d, J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 719.3.

HPLC retention time: 4.761 min.

Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.2mL/L ammonia solution)-acetonitrile; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 0.8mL/min.

SFC retention time 4.329 min.

Separation conditions: Chromatographic column: Chiralpak IG-3 100×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; flow rate: 2.8 mL/min.

Compound 27B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.45 (d, J = 5.0Hz, 1H), 8.04 (s, 1H), 7.48-7.37 (m, 1H), 7.27 (d, J = 5.0Hz, 1H),7.13(dd,J＝10.7,16.9Hz,1H),6.91(d,J＝8.5Hz,1H),6.79(t,J＝8.5Hz,1H),6.31-6.17(m,1H), 5.87-5.75(m,1H),4.95(br s,1H),4.83-4.69(m,1H),4.67-4.49(m,1H),4.39-4.29(m,2H),4.05-3.85(m,2H),3.76(s,3H),3.27- 3.13(m,1H),2.65-2.39(m,3H),2.24-2.13(m,9H),1.77-1.63(m,3H),1.12(d,J＝6.8Hz,3H),1.02(d, J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 719.3.

HPLC retention time 4.775min.

Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.2mL/L ammonia solution)-acetonitrile; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 0.8mL/min.

SFC retention time 4.523 min.

Separation conditions: Chromatographic column: Chiralpak IG-3 100×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; flow rate: 2.8 mL/min.

Compound 27C:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 5.0Hz, 1H), 8.04 (s, 1H), 7.50-7.37 (m, 1H), 7.26 (d, J = 5.0Hz, 1H),7.18-7.11(m,1H),6.91(d,J＝8.3Hz,1H),6.80(t,J＝8.7Hz,1H),6.31-6.17(m,1H),5.86-5.75(m ,1H),4.99-4.93(m,1H),4.75(br d,J＝12.8Hz,1H),4.65-4.40(m,1H),4.36-4.18(m,2H),4.02-3.85(m,2H),3.74(s,3H),3.16(br dd,J ＝3.5,12.3Hz,1H),2.96(td,J＝6.9,13.6Hz,1H),2.86-2.67(m,2H),2.45-2.33(m,6H),1.99(s,3H),1.77- 1.64(m,3H),1.23(d,J＝6.8Hz,3H),1.14-1.09(m,3H).MS(ESI)m/z(M+H) ⁺ =719.3.

HPLC retention time 4.732 min.

Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.2mL/L ammonia solution)-acetonitrile; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 0.8mL/min.

SFC retention time: 8.150 min.

Separation conditions: Chromatographic column: ChiralPak IC-3 150×4.6 mm ID, 3 μm; column temperature: 40° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); isopropanol: 5%-40% 5.5 min, 40% 3 min, 5% 1.5 min; flow rate: 2.5 mL/min.

Compound 27D:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.45 (d, J = 4.8Hz, 1H), 8.05 (s, 1H), 7.48-7.38 (m, 1H), 7.25 (d, J = 5.3Hz, 1H),7.13(dd,J＝10.8,17.1Hz,1H),6.90(d,J＝8.5Hz,1H),6.80(t,J＝8.5Hz,1H),6.32-6.16(m,1H), 5.85-5.76(m,1H),4.96(br s,1H),4.75(br d,J＝12.3Hz,1H),4.67-4.45(m,1H),4.36-4.20(m,2H),4.01-3.86(m,2H),3.71(s,3H),3.27-3.14(m, 1H),2.94(td,J＝6.8,13.6Hz,1H),2.85-2.56(m,2H),2.39-2.24(m,6H),1.99(s,3H),1.76-1.65(m,3H) ,1.24(d,J＝6.8Hz,3H),1.14(d,J＝6.8Hz,3H).MS(ESI)m/z(M+H) ⁺ =719.3.

HPLC retention time: 4.716 min.

Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.2mL/L ammonia solution)-acetonitrile; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 0.8mL/min.

SFC retention time: 6.545 min.

Separation conditions: Chromatographic column: ChiralPak IC-3 150×4.6 mm ID, 3 μm; column temperature: 40° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); isopropanol: 5%-40% 5.5 min, 40% 3 min, 5% 1.5 min; flow rate: 2.5 mL/min.

Example 28: Preparation of Compound 28

Step 1: Preparation of compound 28-2

Compound 28-1 (1 g, 4.61 mmol), ammonium acetate (2.13 g, 27.65 mmol), diacetyl iodobenzene (2.97 g, 9.22 mmol) and sodium dodecyl sulfate (265.74 mg, 921.51 μmol, 263.11 uL) were suspended in water (10 mL), and the system was heated to 70°C for 30 min. After the system was cooled to room temperature (25°C), saturated sodium thiosulfate (5 mL) was added thereto, and the system was stirred at room temperature (25°C) for 15 min, and then extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-5%) to obtain compound 28-2.

¹ H NMR (400MHz, CHLOROFORM-d) δ7.46 (dd, J＝6.0, 8.6Hz, 1H), 7.11 (t, J＝8.4Hz, 1H), 2.44 (s, 3H).

Step 2: Preparation of compound 28-3

At room temperature (20°C), compound 28-2 (760 mg, 3.55 mmol), biboronic acid pinacol ester (1.35 g, 5.33 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (289.97 mg, 355.08 μmol) and potassium acetate (1.05 g, 10.65 mmol) were dissolved in 1,4-dioxane (5 mL). Under nitrogen atmosphere, the system was heated to 100°C and stirred for 16 h. The system was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-5%) to obtain compound 28-3.

Step 3: Preparation of compound 28-5

Compound 28-4 (210 mg, 348.80 μmol), compound 28-3 (136.61 mg, 523.19 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (29.17 mg, 34.88 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (16.28 mg, 34.88 μmol) and potassium carbonate (96.41 mg, 697.59 μmol) were dissolved in a mixed solution of dioxane (3 mL) and water (0.3 mL), and the system was heated to 100 ° C and stirred for 5 h under a nitrogen atmosphere. The system was filtered and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 28-5.

MS (ESI) m/z (M+H) ⁺ = 701.1.

Step 4: Preparation of compound 28-6

Compound 28-5 (150 mg, 214.06 μmol) was dissolved in ethanol (5 mL), hydrazine hydrate (214.31 mg, 4.28 mmol, 208.07 uL) was added thereto, and the system was heated to 80°C for 4 h. The system was cooled to room temperature (25°C) and concentrated, the residue was dissolved in ethyl acetate (10 mL), extracted with 1N hydrochloric acid (20 mL x 3), the aqueous phases were combined, the pH was adjusted to 8 with 1M sodium hydroxide, and then extracted with ethyl acetate (10 mL x 3), the organic phases were combined, the organic phases were washed with water (50 mL x 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 28-6, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 713.4.

Step 5: Preparation of compound 28-7

Compound 28-6 (60 mg, 84.18 μmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL) was added, and the mixture was stirred at 25°C for 1 h. The reaction solution was concentrated to obtain compound 28-7, which was used directly in the next step without further purification. MS (ESI) m/z (M+H) ⁺ = 613.3.

Step 6: Preparation of compound 28

Compound 28-7 (50 mg, 81.61 μmol) was dissolved in tetrahydrofuran (3 mL) and saturated NaHCO ³ aqueous solution (3 mL). Acrylic anhydride (11.32 mg, 89.77 μmol) was added at room temperature (25°C). After the addition, the system was stirred at room temperature (25°C) for 2 h. Water (10 mL) was added to the system for dilution, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile%: 36%-66% 9min), and then purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); mobile phase: [ _CO2- (0.1% ammonia water) methanol]; methanol%: 55%-55%). After concentration, compounds 28A, 28B and 28C were obtained.

Compound 28A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.40 (d, J = 5.0 Hz, 1H), 7.80 (br d, J = 8.8 Hz, 1H), 7.34-7.24 (m, 2H), 7.23-7.19 (m,1H),7.13(dd,J＝10.7,16.9Hz,1H),6.25(dd,J＝1.8,16.8Hz,1H),5.87-5.76(m,1H),4.95(br s,1H) ,4.77(br d,J＝12.5Hz,1H),3.99-3.87(m,2H),3.46(s,3H),3.40(br d,J＝12.3Hz,1H),3.03-2.92(m,2H),2.07(d,J＝5.8Hz,6H),1.69(d,J＝7.0Hz,3H),1.22(d,J＝6.8 Hz,3H),1.13(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 667.3.

HPLC retention time: 6.49 min.

Separation conditions: chromatographic column: WELCH Ultimate C18 150*4.6mm, 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min. SFC retention time 1.661min.

Separation conditions: Chromatographic column: Chiralpak IG-3 50*4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -methanol (0.05% DEA); methanol: 40%-40%; flow rate: 4 mL/min.

Compound 28B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.41 (d, J = 5.0 Hz, 1H), 7.78 (br d, J = 8.8 Hz, 1H), 7.32-7.21 (m, 3H), 7.14 (dd ,J＝10.7,16.9Hz,1H),6.25(dd,J＝1.8,16.8Hz,1H),5.88-5.76(m,1H),5.00-4.96(m,1H),4.77(br d,J＝ 11.8Hz,1H),4.02-3.87(m,2H),3.49(br d,J＝3.3Hz,1H),3.46(s,3H),3.12-2.93(m,2H),2.07(s,3H),1.97(s,3H),1.75(s,1H),1.69(d ,J＝6.8Hz,2H),1.23(d,J＝6.8Hz,3H),1.17(d,J＝6.8Hz,3H).MS(ESI)m/z(M+H) ⁺ ＝667.3.

HPLC retention time: 6.66 min.

Separation conditions: chromatographic column: WELCH Ultimate C18 150*4.6mm, 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min. SFC retention time 4.234min.

Separation conditions: Chromatographic column: Chiralpak IG-3 50*4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -methanol (0.05% DEA); methanol: 40%-40%; flow rate: 4 mL/min.

Compound 28C:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.40 (d, J = 5.0Hz, 1H), 7.77 (br d, J = 9.0Hz, 1H), 7.32-7.22 (m, 3H), 7.13 (dd ,J＝10.7,16.9Hz,1H),6.31-6.20(m,1H),5.86-5.76(m,1H),4.94(br s,1H),4.77(br d,J＝12.5Hz,1H),4.06-3.88(m,2H),3.46(s,4H),2.93(dd,J＝3.5,12.3Hz,1H),2.64-2.54(m,1H),2.25 (s,3H),2.09(s,3H),1.69(d,J＝6.8Hz,3H),1.13(d,J＝6.8Hz,3H),1.01(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 667.3.

HPLC retention time: 6.77 min.

Separation conditions: Chromatographic column: WELCH Ultimate C18 150*4.6mm, 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min SFC retention time 2.725min.

Separation conditions: Chromatographic column: Chiralpak IG-3 50*4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -methanol (0.05% DEA); methanol: 40%-40%; flow rate: 4 mL/min.

Example 29: Preparation of Compound 29

Step 1: Preparation of compound 29-1

Compound 25-3 (700 mg, 1 mmol) and cesium carbonate (977 mg, 3 mmol) were dissolved in N,N-dimethylformamide (20 mL). Compound 26-1 (432 mg, 3 mmol) was added thereto at room temperature (25°C). After the addition, the system was heated to 120°C and stirred for 2 h under a nitrogen atmosphere. The system was filtered and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1/10) to obtain compound 29-1.

MS (ESI) m/z (M+H) ⁺ = 778.2.

Step 2: Preparation of compound 29-2

Compound 29-1 (150 mg, 0.2 mmol) and hydrochloric acid (6N, 7 mL) were added to a mixed solution of methanol (0.6 mL) and tetrahydrofuran (6 mL). The system was heated to 55°C and reacted for 10 min. The system was concentrated to obtain a crude compound 29-2, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 634.2.

Step 3: Preparation of compound 29

Compound 29-2 (140 mg, 0.2 mmol) was dissolved in dichloromethane (10 mL), the system was cooled to 0°C, triethylamine (0.3 mL, 2.1 mmol) and acryloyl chloride (27 mg, 0.3 mmol) were added dropwise, and the system was reacted at 0°C for 0.5 h. The system was quenched with methanol and concentrated to obtain a crude product. The crude product was dissolved in methanol (5 mL), potassium carbonate (140 mg) was added thereto, and after the addition was completed, the system was stirred at room temperature (20°C) for 30 min. The system was adjusted to pH ~ 6 with hydrochloric acid, and extracted with dichloromethane (20 mL) and water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column Welch C18 21.2×250 mm, 10 μm; column temperature: 25° C.; mobile phase: water (10 mM/L NH ₄ HCO ₃ )-acetonitrile; acetonitrile 40%-60% 9 min; flow rate 30 mL/min) to obtain compound 29.

MS (ESI) m/z (M+H) ⁺ = 688.2.

Step 4: Preparation of compounds 29A and 29B

The diastereoisomer compound 29 was purified by SFC (ChiralPak AD, 250×30 mm ID, 10 μm; mobile phase: [CO ₂ -ethanol (0.1% ammonia water)]; ethanol%: 25%; flow rate: 60 mL/min; column temperature: 38° C.) After concentration, compound 29A and compound 29B were obtained.

Compound 29A:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.06 (brs, 1H), 8.37 (d, J = 4.9Hz, 1H), 8.18 (s, 1H), 7.29–7.05 (m, 2H), 6.97 ( dd,J＝16.8,10.6Hz,0.75H),6.79(dd,J＝16.7,10.7Hz,0.25H),6.69–6.46(m,2H),6.07(dd,J＝16.8,2.5Hz,1H) ,5.68(dd,J＝10.5,2.4Hz,1H),4.95(d,J＝13.9Hz,0.25H),4.82–4.66 (m,0.75H),4.54(d,J＝14.0Hz,1H),4.40–4.12(m,2H),3.94(dd,J＝20.5,4.4Hz,1H),3.68(dd,J＝14.2, 4.4Hz,1H),3.14–2.90(m,1H),2.43–2.34(m,2H),2.27–2.08(m,2H),1.97–1.82(m,9H),1.56–1.45(m,3H) ,0.97(dd,J＝6.6,2.2Hz,3H),0.78(t,J＝6.0Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 688.3.

SFC 100% ee. Retention time 3.559 min.

Separation conditions: Chromatographic column: ChiralPak AD-3, 150×4.6 mm ID, 3 μm; Mobile phase: [CO ₂ -ethanol (0.05% DEA)]; Ethanol%: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35°C

Compound 29B:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.18 (brs, 1H), 8.45 (d, J = 4.9Hz, 1H), 8.26 (s, 1H), 7.29–7.20 (m, 2H), 7.04 ( dd,J＝16.8,10.4Hz,0.75H),6.86(dd,J＝17.6,10.4Hz,0.25H),6.72–6.60(m,2H),6.14(d,J＝16.4Hz,1H),5.75 (d,J＝10.7Hz,1H),5.03(d,J＝13.8Hz,0.25H),4.80(d,J＝7.8Hz,0.75H),4.61(d,J＝14.1H z,1H),4.43–4.30(m,1H),4.28–4.15(m,1H),4.04–3.89(m,1H),3.75(dd,J＝14.5,4.4Hz,1H),3.28–3.10( m,2H),2.75–2.65(m,1H),2.39–2.28(m,1H),2.28–2.17(m,1H),2.06–1.96(m,6H),1.81(d,J＝9.5Hz, 3H), 1.53 (d, J = 6.8Hz, 3H), 1.11 (d, J = 6.9Hz, 3H), 0.95 (d, J = 6.6Hz, 3H).

MS (ESI) m/z (M+H) ⁺ = 688.3.

HPLC retention time: 5.269 min.

Separation conditions: chromatographic column: Waters XBridge 4.6*100mm, 3.5μm; column temperature: 40℃; mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile: 5%-95% 7min; flow rate: 1.2mL/min. SFC 100%ee. retention time 4.349min.

Separation conditions: Chromatographic column: ChiralPak AD-3, 150×4.6 mm ID, 3 μm; Mobile phase: [CO ₂ -ethanol (0.05% DEA)]; Ethanol%: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35°C.

Example 30: Preparation of Compound 30

Step 1: Preparation of compound 30-1

Compound 25-2 (286 mg, 0.5 mmol), compound 1-13 (170 mg, 1 mmol), Pd(PPh ₃ ) ₄ (150 mg, 0.125 mmol), potassium carbonate (138 mg, 1 mmol) were dissolved in a mixed solution of dioxane (18 mL) and water (1.8 mL). Under a nitrogen atmosphere, the system was heated to 100° C. and stirred for 2 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 30-1.

MS (ESI) m/z (M+H) ⁺ = 677.2.

Step 2: Preparation of compound 30-2

Compound 30-1 (700 mg, 1 mmol) and cesium carbonate (977 mg, 3 mmol) were dissolved in N,N-dimethylformamide (20 mL). Compound 26-1 (432 mg, 3 mmol) was added thereto at room temperature (25°C). After the addition, the system was heated to 120°C and stirred for 2 h under a nitrogen atmosphere. The system was filtered and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1/10) to obtain compound 30-2.

MS (ESI) m/z (M+H) ⁺ = 748.2.

Step 3: Preparation of compound 30-3

Compound 30-2 (80 mg, 0.107 μmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at 25° C. for 1 h. The reaction solution was concentrated to obtain compound 30-3, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 648.4.

Step 4: Preparation of compound 30

Compound 30-3 (70 mg, 0.107 mmol) was dissolved in dichloromethane (10 mL), the system was cooled to 0°C, triethylamine (0.1 mL, 0.7 mmol) and acryloyl chloride (14 mg, 0.2 mmol) were added dropwise, and the system was reacted at 0°C for 0.5 h. The system was quenched with water and concentrated to obtain a crude product, which was extracted with dichloromethane (10 mL) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column Welch C18 21.2×250 mm, 10 μm; column temperature: 25° C.; mobile phase: water (10 mM/L NH ₄ HCO ₃ )-acetonitrile; acetonitrile 45%-75% 9 min; flow rate 30 mL/min) to obtain compound 30.

MS (ESI) m/z (M+H) ⁺ = 702.2.

Step 5: Preparation of compounds 30A and 30B

The diastereoisomer compound 30 was purified by SFC (ChiralPak AD, 250×30 mm ID, 10 μm; mobile phase: [CO ₂ -ethanol (0.1% ammonia water)]; ethanol%: 35%; flow rate: 80 mL/min; column temperature: 38° C.) After concentration, compound 30A and compound 30B were obtained.

Compound 30A:

¹ H NMR (400MHz, Chloroform-d) δ8.51 (t, J＝4.5Hz, 1H), 8.25 (s, 1H), 7.45–7.27 (m, 1H), 7.18–6.98 (m, 2H), 6.88 –6.61(m,2H),6.34(dd,J＝16.9,1.9Hz,1H),5.79(dt,J＝10.7,1.7Hz,1H),5.07(d,J＝7.3Hz,1H),4.77( d,J＝13.9Hz,1H),4. 64–4.37(m,1H),3.80(dt,J＝14.1,4.7Hz,1H),3.68(d,J＝26.8Hz,3H),3.34–3.02(m,2H),2.48(dt,J＝ 13.7,7.1Hz,1H),2.30–2.16(m,4H),2.02(d,J＝1.7Hz,3H),1.75–1.46(m,9H),1.19(t,J＝6.5Hz,3H), 0.95(dd,J＝12.9,6.7Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 702.3.

SFC 100% ee. Retention time 3.619 min.

Separation conditions: Chromatographic column: ChiralPak AD-3, 150×4.6 mm ID, 3 μm; Mobile phase: [CO ₂ -ethanol (0.05% DEA)]; Ethanol%: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35°C.

Compound 30B:

¹ H NMR (400MHz, Chloroform-d) δ8.51 (dd, J＝4.9, 1.9Hz, 1H), 8.26 (s, 1H), 7.32 (td, J＝8.4, 6.6Hz, 1H), 7.15–6.98 (m,2H),6.83–6.66(m,2H),6.34(dd,J＝16.9,2.0Hz,1H),5.79(dt,J＝10.8,1.5Hz,1H),5.13–5.01(m,1H ),4.77(d,J＝14.0Hz ,1H),4.53–4.35(m,1H),3.79(dt,J＝14.1,4.3Hz,1H),3.69(d,J＝10.7Hz,3H),3.43–3.17(m,2H),2.70( h,J＝6.7Hz,1H),2.48–2.02(m,4H),1.97–1.83(m,3H),1.73–1.52(m,9H),1.21(dd,J＝6.8,5.0Hz,3H) ,1.05(dd,J＝8.0,6.7Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 702.3.

SFC 100% ee. Retention time 4.635 min.

Separation conditions: Chromatographic column: ChiralPak AD-3, 150×4.6 mm ID, 3 μm; Mobile phase: [CO ₂ -ethanol (0.05% DEA)]; Ethanol%: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35°C

Example 31: Preparation of Compound 31

Step 1: Preparation of compound 31-2

Potassium nitrate (10.49 g, 103.72 mmol) was dissolved in concentrated sulfuric acid (80 mL), and the system was stirred at room temperature (20°C) for 1 h. Compound 31-1 (10 g, 57.62 mmol) was added in batches. After the addition, the system was heated to (80°C) and stirred for 2 h. Ice water (200 mL) was added to the system for quenching, and then filtered. The filter cake was washed with water (20 mL x 2) and dried to obtain compound 31-2.

Step 2: Preparation of compound 31-3

Compound 31-2 (12.6 g, 57.65 mmol) was dissolved in 20% aqueous sulfuric acid solution (200 mL), and the system was heated to (85°C) and stirred for 16 h. After the system was cooled to room temperature (20°C), it was diluted with water (1 L), extracted with ethyl acetate (2x500 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 31-3.

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 7.77 (d, J = 7.8 Hz, 1H).

Step 3: Preparation of compound 31-4

Compound 31-3 (13 g, 54.73 mmol) was dissolved in methanol (120 mL), and dichlorothionyl (26.04 g, 218.91 mmol, 15.88 mL) was added thereto. After the addition, the system was heated to 70°C and stirred for 16 h. After the system was cooled to room temperature (20°C), it was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-10%) to obtain compound 31-4.

Step 4: Preparation of compound 31-5

Compound 31-4 (6 g, 23.85 mmol) was dissolved in a mixed solvent of ethyl acetate (50 mL) and dichloromethane (50 mL), and stannous chloride dihydrate (26.91 g, 119.25 mmol) was added thereto. After the addition, the system was stirred at room temperature (20°C) for 16 h. The system was filtered and the filtrate was concentrated to obtain compound 31-5.

¹ H NMR (400 MHz, CHLOROFORM-d) δ＝7.50 (dd, J＝2.3, 9.8 Hz, 1H), 5.74 (br s, 2H), 3.92 (s, 3H). Step 5: Preparation of Compound 31-6

Compound 31-5 (8 g, 36.10 mmol), cuprous iodide (6.88 g, 36.10 mmol), potassium iodide (11.99 g, 72.21 mmol) were dissolved in acetonitrile (100 mL), and tert-butyl nitrite (11.17 g, 108.31 mmol, 12.88 mL) was added thereto at 0°C. Under a nitrogen atmosphere, the system was heated to 80°C and stirred for 2 h. After the system was cooled to room temperature (20°C), sodium thiosulfate aqueous solution (100 mL) was added thereto to quench, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-7%) to obtain compound 31-6.

¹ H NMR (400MHz, DMSO-d6) δ = 7.82-7.74 (m, 1H), 3.89 (s, 3H).

Step 6: Preparation of compound 31-7

At room temperature (20°C), compound 31-6 (7g, 21.05mmol), compound 3-9 (3.51g, 23.37mmol), Pd ₂ (dba) ₃ (1.93g, 2.11mmol), Xantphos (1.22g, 2.11mmol), cesium carbonate (13.72g, 42.11mmol) were dissolved in toluene (100mL), and the system was heated to 100°C and stirred for 16h under nitrogen atmosphere. The system was cooled to room temperature and concentrated, and the residue was extracted with water (50mL) and ethyl acetate (30mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-7%) to obtain compound 31-7.

¹ H NMR (400MHz, DMSO-d6) δ=8.74-8.72(m,1H),8.28-8.26(m,1H),7.72-7.68(m,1H),7.11-7.08(m,1H),3.84( s,3H),3.26-3.21(m,1H),2.08(s,3H),1.12-1.04(m,6H).

Step 7: Preparation of compound 31-8

At 0°C, compound 31-7 (3 g, 8.46 mmol) was dissolved in N, N-dimethylformamide (30 mL), and NaH (2.03 g, 50.74 mmol, 60% purity) was added in batches. After the addition, the system was stirred at 0°C for 30 min. Acetyl chloride (3.98 g, 50.74 mmol, 3.62 mL) was added dropwise to the system at 0°C. After the addition, the system was heated to room temperature (20°C) under a nitrogen atmosphere and reacted for 16 h. Water (300 mL) was added to the system to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-100%) to obtain compound 31-8.

MS (ESI) m/z (M+H) ⁺ = 397.0.

Step 8: Preparation of compound 31-9

At room temperature (20°C), compound 31-8 (1.5 g, 3.78 mmol) was dissolved in toluene (40 mL), and potassium tert-butoxide (1 M, 11.34 mL) was added thereto. After the addition, the system was reacted at room temperature (20°C) for 20 min under a nitrogen atmosphere. Water (10 mL) was added to the system to quench the reaction, the pH was adjusted to neutral with 1N hydrochloric acid, and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 31-9, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 364.9.

Step 9: Preparation of compound 31-10

Compound 31-9 (1.2 g, 3.29 mmol) was dissolved in glacial acetic acid (15 mL). Nitric acid (2.49 g, 39.48 mmol, 1.78 mL) was added dropwise to the system at room temperature (20 ° C). After the addition was completed, the system was heated to 80 ° C and stirred for 2 h. After the system was cooled to room temperature, most of the glacial acetic acid was removed by concentration, and the residue was poured into ice water (10 mL). The precipitate was precipitated and filtered. The filter cake was washed with water and dried to obtain compound 31-10, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 409.9.

Step 10: Preparation of compound 31-11

Compound 31-10 (0.9 g, 2.20 mmol) and N,N-diisopropylethylamine (851.59 mg, 6.59 mmol, 1.15 mL) were dissolved in acetonitrile (10 mL). Phosphorus oxychloride (1.01 g, 6.59 mmol, 612.31 uL) was added thereto at room temperature (20 ° C). After the addition, the system was heated to 80 ° C and stirred for 2 h. After the system was cooled to room temperature (20 ° C), it was poured into water (20 mL) and extracted with ethyl acetate (3x10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 31-11, which was directly used in the next step without further purification.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.64 (d, J = 5.0Hz, 1H), 7.89 (dd, J = 2.0, 8.5Hz, 1H), 7.18 (d, J = 4.8Hz, 1H), 2.69-2.58(m,1H),2.12(s,3H),1.26-1.12(m,6H).

Step 11: Preparation of compound 31-12

Compound 31-11 (0.8 g, 1.87 mmol), 7-1 (579.10 mg, 2.24 mmol), N,N-diisopropylethylamine (362.17 mg, 2.80 mmol, 488.10 uL) were dissolved in tetrahydrofuran (10 mL), and the system was heated to 70 ° C and stirred for 20 h. The system was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-40%) to obtain compound 31-12.

MS (ESI) m/z (M+H) ⁺ = 650.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.60 (dd, J = 2.1, 4.9Hz, 1H), 8.15-7.76 (m, 1H), 7.15 (dd, J = 5.1, 6.7Hz, 1H), 4.60 -4.41(m,2H),4.31(br s,1H),4.00(br s,1H),3.81(d,J＝1.0Hz,3H),3.63-3.48(m,1H),3.24-3.07(m ,1H),2.77-2.55(m,1H),2.10-2.02(m,3H),1.51(d,J＝1.3Hz,9H),1.35(t,J＝6.0Hz,3H),1.25-1.13( m,6H)

Step 12: Preparation of compound 31-13

Compound 31-12 (0.9 g, 1.38 mmol) and iron powder (231.95 mg, 4.15 mmol) were dissolved in acetic acid (15 mL). Under nitrogen atmosphere, the system was heated to 85 °C and stirred for 1 h. The system was filtered through diatomaceous earth, the filtrate was concentrated, the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 31-13. It was used directly in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 588.1.

Step 13: Preparation of compound 28-4

Compound 31-13 (800 mg, 1.36 mmol) and potassium carbonate (376.04 mg, 2.72 mmol) were dissolved in acetone (10 mL). At room temperature (20 ° C), iodomethane (1.93 g, 13.60 mmol, 846.92 uL) was added. After the addition, the system was heated to 40 ° C and stirred for 16 h under a nitrogen atmosphere. The system was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 28-4.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.62 (d, J = 5.0Hz, 1H), 7.59 (br d, J = 9.0Hz, 1H), 7.17 (dd, J = 4.8, 15.8Hz, 1H) ,4.90(br d,J＝12.3Hz,1H),4.64-4.29(m,1H),3.55-3.38(m,4H),3.14-2.92(m,2H),2.88-2.35(m,1H), 2.21-2.00(m,3H),1.45-1.59(m,12H),1.26-1.01(m,6H).

Step 14: Preparation of compound 31-14

Compound 28-4 (100 mg, 166.09 μmol), o-fluorophenylboric acid (46.48 mg, 332.19 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (13.89 mg, 16.61 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (7.75 mg, 16.61 μmol) and potassium carbonate (45.91 mg, 332.19 μmol) were dissolved in a mixed solution of dioxane (1 mL) and water (0.1 mL). Under a nitrogen atmosphere, the system was heated to 100 ° C and stirred for 5 h. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-40%) to obtain compound 31-14.

MS (ESI) m/z (M+H) ⁺ = 662.6.

Step 15: Preparation of compound 31-15

Compound 31-14 (100 mg, 151.12 μmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (5 M, 5 mL) was added thereto. After the addition was completed, the system was stirred at room temperature (25° C.) for 2 h. The system was concentrated to obtain compound 31-15, which was directly used in the next reaction without further purification.

MS (ESI) m/z (M+H) ⁺ = 562.1.

Step 16: Preparation of compound 31

Compound 31-15 (90 mg, 150.49 μmol, hydrochloride) was dissolved in tetrahydrofuran (5 mL) and sodium bicarbonate (63.21 mg,

752.44μmol) aqueous solution (5mL), to which was added a tetrahydrofuran solution of acrylic anhydride (0.5M, 361.17uL). After the addition was complete, the system was reacted at room temperature (20°C) for 1h. The system was quenched with methanol (0.1mL), extracted with ethyl acetate (5mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30mm*3μm, mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile 46%-76% 9min) to obtain compound 31.

MS (ESI) m/z (M+H) ⁺ = 616.4.

Step 17: Preparation of compounds 31A and 31B

The diastereoisomer compound 31 was purified by SFC (Phenomenex-Cellulose-2 (250 mm*30 mm, 10 μm); mobile phase: [CO ₂ -methanol (0.1% ammonia water)]; methanol%: 50%). After concentration, compound 31A and compound 31B were obtained.

Compound 31A:

¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.48 (d, J = 4.8Hz, 1H), 7.74 (d, J = 8.5Hz, 1H), 7.49 (s, 1H), 7.41-7.12 (m, 5H),6.33-6.18(m,1H),5.90-5.74(m,1H),4.78(m,2H),4.04-3.85(m,2H),3.52-3.45(m,4H),3.04-2.87( m,1H),2.58-2.52(m,1H),2.23(s,3H),1.77-1.63(m,3H),1.20-1.03(m,6H).

MS (ESI) m/z (M+H) ⁺ = 616.2

HPLC retention time: 4.12 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min SFC retention time 5.115min.

Separation conditions: Chromatographic column: Cellulose 2 150*4.6 mm ID, 5 μm; Column temperature: 35° C.; Mobile phase: CO ₂ -methanol (0.05% DEA); Methanol: 40%-40%; Flow rate: 2.5 mL/min.

Compound 31B:

¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.47 (d, J = 4.8Hz, 1H), 7.75 (d, J = 9.5Hz, 1H), 7.56-7.47 (m, 1H), 7.42-7.03 ( m,5H),6.33-6.22(m,1H),5.88-5.77(m,1H),4.82-4.50(m,2H),4.01-3.85(m,2H),3.53-4.35(m,4H), 3.09-2.89(m,2H),2.00(d,J＝6.0Hz,3H),1.76-1.64(m,3H),1.29-1.13(m,6H).

MS (ESI) m/z (M+H) ⁺ = 616.2.

HPLC retention time: 4.11 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min SFC retention time 7.223min

Separation conditions: Chromatographic column: Cellulose 2 150*4.6 mm ID, 5 μm; Column temperature: 35° C.; Mobile phase: CO ₂ -methanol (0.05% DEA); Methanol: 40%-40%; Flow rate: 2.5 mL/min.

Example 32: Preparation of Compound 32

Step 1: Preparation of compound 32-2

Compound 28-4 (120 mg, 199.31 μmol), compound 32-1 (70.15 mg, 398.62 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (16.67 mg, 19.93 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (9.30 mg, 19.93 μmol) and potassium carbonate (55.09 mg, 398.62 μmol) were dissolved in a mixed solution of dioxane (1 mL) and water (0.1 mL). Under a nitrogen atmosphere, the system was heated to 100°C and stirred for 5 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-60%) to obtain compound 32-2.

MS (ESI) m/z (M+H) ⁺ = 698.3.

Step 2: Preparation of compound 32-3

Compound 32-2 (102 mg, 146.18 μmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (5 M, 5 mL) was added thereto. After the addition was complete, the system was stirred at room temperature (25° C.) for 2 h. The system was concentrated to obtain compound 32-3, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 598.1.

Step 3: Preparation of compound 32

Compound 32-3 (92 mg, 145.08 μmol, hydrochloride) was dissolved in tetrahydrofuran (5 mL) and an aqueous solution (5 mL) of sodium bicarbonate (121.88 mg, 1.45 mmol), and a tetrahydrofuran solution of acrylic anhydride (0.5 M, 377.21 uL) was added dropwise. After the addition was completed, the system was reacted at room temperature (20°C) for 2 h. The system was quenched with methanol (0.1 mL), extracted with ethyl acetate (5 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30 mm*3 μm, mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; acetonitrile 39%-69% 9 min) to obtain compounds 32A, 32B, 32C and 32D.

Compound 32A:

¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.41 (d, J = 5.0Hz, 1H), 7.82 (d, J = 8.0Hz, 1H), 7.55 (d, J = 9.0Hz, 1H), 7.46 (s,1H),7.37(d,J＝8.5Hz,1H),7.28(d,J＝5.3Hz,1H),7.20-6.74(m,1H),6.27(d,J＝18.8H z,1H),5.90-5.74(m,1H),4.82-4.50(m,2H),4.07-3.91(m,2H),3.52-3.45(m,4H),2.99-2.60(m,2H), 2.23(s,1H),2.18(s,3H),1.78-1.65(m,3H),1.20-0.97(m,6H).

MS (ESI) m/z (M+H) ⁺ = 652.2.

HPLC retention time: 3.49 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40°C; Mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min Compound 32B:

¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.42 (d, J = 4.8 Hz, 1H), 7.82 ( d, J = 8.0 Hz, 1H), 7.55 ( d, J = 8.8 Hz, 1H), 7.48 (s,1H),7.37(d,J＝8.5Hz,1H),7.23(d,J＝4.8Hz,1H),7.20-6.80(m,1H),6.33-6.24(m, 1H),5.88-5.79(m,1H),4.82-4.50(m,2H),4.04-3.85(m,2H),3.54-3.37(m,4H),3.10-2.90(m,2H),2.19( s,3H),2.05(s,3H),1.77-1.66(m,3H),1.27-1.12(m,6H).

MS (ESI) m/z (M+H) ⁺ = 652.2.

HPLC retention time: 3.53 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min.

Compound 32C:

¹ H NMR (400 MHz, METHANOL-d ₄ )δ＝8.43(d,J＝5.0Hz,1H),7.80(d,J＝9.5Hz,1H),7.59-7.48(m,2H),7.38(d,J＝8.5Hz,1H),7.25(d,J＝5.3Hz,1H),7.21-6.83(m,1H),6.29-6.25(m,1H) ,5.88-5.78(m,1H),4.82-4.50(m,2H),4.03-3.86(m,2H),3.54-3.39(m,4H),3.15-2.90(m,2H),2.18(s,3H),2.01(s,3H),1.77-1.66(m,3H),1.3 0-1.07(m,6H).

MS (ESI) m/z (M+H) ⁺ = 652.2.

HPLC retention time: 3.66 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min.

Compound 32D:

¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.42 (d, J = 5.0Hz, 1H), 7.80 (d, J = 10.0Hz, 1H), 7.58-7.50 (m, 2H), 7.37 (d, J＝8.5Hz,1H),7.26(d,J＝4.8Hz,1H),7.18-7.12(m,1H),6.35-6.21(m,1H),5.91-5.75(m ,1H),4.82-4.50(m,2H),4.07-3.87(m,2H),3.50-3.38(m,4H),2.99-2.87(m,1H),2.72-2.51(m,1H),2.26 (s,3H),2.18(s,3H),1.79-1.65(m,3H),1.19-0.96(m,6H).

MS (ESI) m/z (M+H) ⁺ = 652.2.

HPLC retention time 3.70min

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min.

Example 33: Preparation of Compound 33

Step 1: Preparation of compound 33-2

Compound 28-4 (100 mg, 166.09 μmol), compound 33-1 (68.15 mg, 249.14 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (13.89 mg, 16.61 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (7.75 mg, 16.61 μmol) and potassium carbonate (68.86 mg, 498.27 μmol) were dissolved in a mixed solution of dioxane (2 mL) and water (0.2 mL). Under a nitrogen atmosphere, the system was heated to 100 ° C and stirred for 5 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain compound 33-2.

MS (ESI) m/z (M+H) ⁺ = 677.3.

Step 2: Preparation of compound 33-3

Compound 33-2 (95 mg, 140.38 μmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (5 M, 5 mL) was added thereto. After the addition was complete, the system was stirred at room temperature (25° C.) for 2 h. The system was concentrated to obtain compound 33-3, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 577.2.

Step 3: Preparation of compound 33

Compound 33-3 (90 mg, 146.80 μmol, hydrochloride) was dissolved in tetrahydrofuran (5 mL) and an aqueous solution (5 mL) of sodium bicarbonate (12.33 mg, 146.80 μmol), and a tetrahydrofuran solution of acrylic anhydride (0.5 M, 352.32 uL) was added dropwise. After the addition was completed, the system was reacted at room temperature (20°C) for 2 h. The system was quenched with methanol (0.1 mL), extracted with ethyl acetate (5 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30 mm*3 μm, mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; acetonitrile 42%-72% 9

min) to give compounds 33A and 33B.

Step 4: Preparation of compounds 33A-1 and 33A-2

The diastereoisomer compound 33A was purified by SFC (Phenomenex-Cellulose-2 (250 mm*30 mm, 10 μm); mobile phase: [CO ₂ -methanol (0.1% ammonia water)]; methanol%: 45%). After concentration, compound 33A-1 and compound 33A-2 were obtained.

Compound 33A-1:

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 8.46 (d, J = 4.8Hz, 1H), 7.57 (d, J = 8.3Hz, 1H), 7.26 (d, J = 5.0Hz, 1H), 7.15 -6.83(m,2H),6.50(d,J＝8.3Hz,1H),6.35(t,J＝8.8Hz,1H),6.21-6.09(m,1H),5.82-5.64(m,1H), 5.21(br s,2H),4.85-4.78(m,1H),4.64-4.37(m,1H),3.99-3.88(m,1H),3.79-3.71(m,1H),3.45-3.35(m,4H), 2.94-2.73(m,1H),2.71-2.58(m,1H),2.06(s,3H),1.63-1.48(m,3H),1.10-0.91(m,6H).

MS (ESI) m/z (M+H) ⁺ = 631.2.

HPLC retention time 3.70min

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min SFC retention time 5.22min.

Separation conditions: Chromatographic column: Cellulose 2 150*4.6 mm ID, 5 μm; Column temperature: 35° C.; Mobile phase: CO ₂ -methanol (0.05% DEA); Methanol: 40%-40%; Flow rate: 2.5 mL/min.

Compound 33A-2:

¹ H NMR (400 MHz, METHANOL-d ₄ )δ＝8.46(d,J＝4.8Hz,1H),7.74(d,J＝7.8Hz,1H),7.27(d,J＝5.0Hz,1H),7.23-6.83(m,2H),6.61(d,J＝8.5Hz,1H),6.41(t,J＝8.9Hz,1H),6.31-6.21(m,1 H),5.91-5.74(m,1H),4.82-4.50(m,2H),3.99-3.84(m,2H),3.51-3.43(m,4H),2.98-2.92(m,2H),2.04(s,3H),1.76-1.64(m,3H),1.27-1.09(m,6 H).

MS (ESI) m/z (M+H) ⁺ = 631.1.

HPLC retention time: 3.67 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min.

SFC retention time: 6.417 min.

Separation conditions: Chromatographic column: Cellulose 2 150*4.6 mm ID, 5 μm; Column temperature: 35° C.; Mobile phase: CO ₂ -methanol (0.05% DEA); Methanol: 40%-40%; Flow rate: 2.5 mL/min.

Step 5: Preparation of compounds 33B-1 and 33B-2

The diastereoisomer compound 33B was purified by SFC (Phenomenex-Cellulose-2 (250 mm*30 mm, 10 μm); mobile phase: [CO ₂ -methanol (0.1% ammonia water)]; methanol%: 45%). After concentration, compound 33B-1 and compound 33B-2 were obtained.

Compound 33B-1:

¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.47 (d, J = 5.0Hz, 1H), 7.72 (d, J = 9.8Hz, 1H), 7.30 (d, J = 4.8Hz, 1H), 7.19 -7.08(m,2H),6.60(d,J＝8.0Hz,1H),6.40(t,J＝8.8Hz,1H),6.28-6.22(m,1H),5.88 -5.81(m,1H),4.82-4.50(m,2H),4.07-3.89(m,2H),3.55-3.36(m,4H),3.00-2.85(m,1H),2.62-2.46(m, 1H),2.25(s,3H),1.77-1.63(m,3H),1.15-0.98(m,6H).

MS (ESI) m/z (M+H) ⁺ = 631.1.

HPLC retention time: 3.82 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min SFC retention time 4.576min.

Separation conditions: Chromatographic column: Cellulose 2 150*4.6 mm ID, 5 μm; Column temperature: 35° C.; Mobile phase: CO ₂ -methanol (0.05% DEA); Methanol: 40%-40%; Flow rate: 2.5 mL/min.

Compound 33B-2:

¹ H NMR (400 MHz, METHANOL-d ₄ )δ＝8.47(d,J＝5.0Hz,1H),7.73(d,J＝8.8Hz,1H),7.28(d,J＝5.0Hz,1H),7.21-7.10(m,2H),6.59(d,J＝8.3Hz,1H),6.40(t,J＝8.7Hz,1H),6.31-6.23(m,1 H),5.88-5.76(m,1H),4.81-4.50(m,2H),4.02-3.84(m,2H),3.53-3.38(m,4H),3.09-2.93(m,2H),1.97(s,3H),1.76-1.65(m,3H),1.27-1.11(m,6 H).

MS (ESI) m/z (M+H) ⁺ = 631.1.

HPLC retention time: 3.87 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min SFC retention time 6.411min.

Separation conditions: Chromatographic column: Cellulose 2 150*4.6 mm ID, 5 μm; Column temperature: 35° C.; Mobile phase: CO ₂ -methanol (0.05% DEA); Methanol: 40%-40%; Flow rate: 2.5 mL/min.

Example 34: Preparation of Compound 34

Step 1: Preparation of compound 34-2

Compound 16-3 (120 mg, 180.80 μmol) was dissolved in N,N-dimethylformamide (2 mL), and sodium hydride (60 mg, 1.50 mmol, 60%) was added thereto. After the addition, the reaction was stirred at room temperature (25°C) for 0.5 h, and compound 34-1 (178.47 mg, 722.66 μmol, HBr salt) was added thereto, and the reaction was stirred at room temperature (25°C) for 2 h. The reaction solution was quenched with 10 drops of saturated ammonium chloride solution, diluted with ethyl acetate (30 mL), washed with water (10 mL) and saturated sodium chloride solution (10 mL) in sequence, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 34-2, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 749.3.

Step 2: Preparation of compound 34-3

Compound 34-2 (150 mg, 200.30 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (390 mg, 1.56 mmol, 0.15 mL) was added thereto, and the reaction was stirred at room temperature (20°C) for 5 h. The reaction solution was quenched with methanol (5 mL), stirred for 10 min, and concentrated under reduced pressure to obtain crude product 34-3, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 635.2.

Step 3: Preparation of compound 34

Compound 34-3 (150 mg, 209.60 μmol, HBr salt) was dissolved in tetrahydrofuran (2.5 mL) and an aqueous solution (2.5 mL) of sodium bicarbonate (5.40 g, 64.28 mmol), and a tetrahydrofuran solution (0.5 mL) of acrylic anhydride (29.87 mg, 236.85 μmol) was added dropwise. After the addition was completed, the system was stirred at room temperature (20°C) for 2 h. Methanol (1 mL) and an aqueous solution of potassium carbonate (2M, 1.50 mL) were added to the system, and the system was stirred at room temperature (20°C) for 1.5 h. Water (10 mL) was added to the system for dilution, and the pH was adjusted to ~6 with 1N HC, extracted with ethyl acetate (20 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column Xtimate C18 100*30mm*3μm, mobile phase: water (0.225% formic acid)-acetonitrile; acetonitrile 25%-35% 8min) and then purified by SFC (separation conditions: chromatographic column DAICELCHIRALPAK IC

(250 mm*30 mm, 5 μm); mobile phase: [CO ₂ -ethanol (0.1% ammonia water)]; ethanol%: 35%). Compounds 34A and 34B were obtained.

Compound 34A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.42 (d, J = 5.1 Hz, 1H), 7.59 (br d, J = 9.7 Hz, 1H), 7.29-7.16 (m, 2H), 6.91-6.79 (m,1H),6.73-6.56(m,2H),6.28(dd,J＝1.8,16.8Hz,1H),5.82(br d,J＝10.6Hz,1H),4.95-4.91(m,1H) ,4.63(br d,J＝13.2Hz,1H),4.53(br s,1H),4.19(br s,1H),3.79(br s,1H),3.57(br dd,J＝7.7,11.7Hz, 2H),3.24(br s,3H),3.10-2.90(m,3H),2.83-2.40(m,7H),2.11(br s,2H),2.05(s,3H),1.77(br s,3H),1.20-1.03( m,6H).

MS (ESI) m/z (M+H) ⁺ = 689.3.

LCMS retention time 2.483 min.

Separation conditions: Chromatographic column: Xtimate C18 2.1*30mm, 3μm; Column temperature: 50℃; Mobile phase: Water (1.5mL/4L trifluoroacetic acid solution)-Acetonitrile (0.75mL/4L trifluoroacetic acid solution); Acetonitrile: 10%-80% 6min, 80% 0.5min; Flow rate: 0.8mL/min.

Compound 34B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.43 (d, J = 4.0Hz, 1H), 7.59 (br d, J = 9.7Hz, 1H), 7.32-7.15 (m, 2H), 6.85 (br s,1H),6.72-6.55(m,2H),6.28(dd,J＝1.7,16.6Hz,1H),5.82(br d,J＝10.1Hz,1H),5.04-4.95(m,1H), 4.79-4.38(m,2H),4.22(br s,1H),3.76(br s,1H),3.64-3.48(m,2H),3.28-3.11(m,3H),3.09-2.91(m,3H),2.86-2.45(m,7H),2.11(brd,J＝7.9Hz, 1H),2.05(d,J＝5.7Hz,3H),1.77(br s,3H),1.24-1.05(m,6H).MS(ESI)m/z(M+H) ⁺ =689.2.

MS (ESI) m/z (M+H) ⁺ = 689.2.

LCMS retention time 2.676 & 2.730 min.

Separation conditions: Chromatographic column: Xtimate C18 2.1*30mm, 3μm; Column temperature: 50℃; Mobile phase: Water (1.5mL/4L trifluoroacetic acid solution)-Acetonitrile (0.75mL/4L trifluoroacetic acid solution); Acetonitrile: 10%-80% 6min, 80% 0.5min; Flow rate: 0.8mL/min.

Example 35: Preparation of Compound 35

Step 1: Preparation of compound 35-2

Compound 16-3 (150 mg, 226.00 μmol) was dissolved in N, N-dimethylformamide (3 mL), sodium hydride (50 mg, 1.25 mmol, 60%) was added thereto, and the reaction was stirred at room temperature (25°C) for 0.5 h, compound 35-1 (170 mg, 671.27 μmol) was added thereto, and the reaction was stirred at room temperature (25°C) for 1 h. The reaction solution was quenched with 3 drops of saturated ammonium chloride solution, diluted with ethyl acetate (30 mL), washed with water (10 mL) and saturated sodium chloride solution (10 mL) in sequence, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-7%) to obtain compound 35-2.

MS (ESI) m/z (M+H) ⁺ = 836.1.

Step 2: Preparation of compound 35-3

Compound 35-2 (115 mg, 137.55 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (260 mg, 1.04 mmol, 0.1 mL) was added thereto, and the reaction was stirred at room temperature (20 ° C) for 6 h. The reaction solution was quenched with methanol (5 mL) and stirred for 10 min. After adding dichloromethane (30 mL) to the system, it was washed with saturated sodium bicarbonate aqueous solution (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude product 35-3, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 608.3.

Step 3: Preparation of compounds 35A and 35B

Compound 35-3 (93.8 mg, 139.88 μmol) was dissolved in tetrahydrofuran (2 mL) and an aqueous solution (2 mL) of sodium bicarbonate (4.32 g, 51.42 mmol), and a tetrahydrofuran solution (0.5 mL) of acrylic anhydride (29.87 mg, 236.85 μmol) was added dropwise. After the addition was completed, the system was stirred at room temperature (20°C) for 2 h. Methanol (1 mL) and an aqueous potassium carbonate solution (2M, 1 mL) were added to the system, and the system was stirred at room temperature (20°C) for 1.5 h. Water (10 mL) was added to the system for dilution, and the pH was adjusted to ~6 with 1N HC, extracted with ethyl acetate (20 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-performance preparative liquid phase (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30mm*3μm, mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile 43%-73% 9min) to obtain compounds 35A and 35B.

Compound 35A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.40 (d, J = 4.9 Hz, 1H), 7.56 (br d, J = 9.4 Hz, 1H), 7.25-7.15 (m, 2H), 6.91-6.79 (m,1H),6.71-6.56(m,2H),6.28(dd,J＝1.7,16.7Hz,1H),5.81(br d,J＝10.6Hz,1H),5.02-4.89(m,1H) ,4.69-4.45(m,1H),4.35-3.99(m,1H),3.84-3.58(m,4H),3.56-3.43(m,2H),3.38-3.33(m,1H),3.25(br s,1H),2.99(br d,J＝9.8Hz,1H),2.68(tt,J＝6.7,13.2Hz,1H),2.04(d,J＝2.7Hz,3H),1.90-1.80(m, 2H),1.79-1.63(m,3H),1.18-1.03(m,6H).

MS (ESI) m/z (M+H) ⁺ = 662.2.

LCMS retention time 2.835 min.

Separation conditions: Chromatographic column: Xtimate C18 2.1*30mm, 3μm; Column temperature: 50℃; Mobile phase: Water (1.5mL/4L trifluoroacetic acid solution)-Acetonitrile (0.75mL/4L trifluoroacetic acid solution); Acetonitrile: 10%-80% 6min, 80% 0.5min; Flow rate: 0.8mL/min.

Compound 35B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.40 (d, J = 4.9 Hz, 1H), 7.55 (br d, J = 9.2 Hz, 1H), 7.27-7.15 (m, 2H), 6.84 (br s,1H),6.71-6.55(m,2H),6.28(br d,J＝16.5Hz,1H),5.82(brs,1H),5.02-4.91(m,1H),4.60(br s,1H) ,4.27-3.95(m,1H),3.93-3.54(m,4H),3.48(brd,J＝12.5Hz,2H),3.35(br s,1H),3.25(br s,1H),3.00(br s,1H),2.67(tt,J＝6.6,12.9Hz,1H),2.04(d,J＝10.7Hz,3H),1.91-1.80(m,2H),1.79-1.60(m,3H),1.20 -1.04(m,6H).

MS (ESI) m/z (M+H) ⁺ = 662.3.

LCMS retention time 2.994 min.

Separation conditions: Chromatographic column: Xtimate C18 2.1*30mm, 3μm; Column temperature: 50℃; Mobile phase: Water (1.5mL/4L trifluoroacetic acid solution)-acetonitrile (0.75mL/4L trifluoroacetic acid solution); Acetonitrile: 10%-80% 6min, 80% 0.5min; Flow rate: 0.8mL/min.

Step 4: Preparation of compounds 35A-1 and 35A-2

The diastereoisomer compound 35A was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 μm); mobile phase: [CO ₂ -methanol (0.1% ammonia water)]; methanol%: 40%). After concentration, compound 35A-1 and compound 35A-2 were obtained.

Compound 35A-1:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.41 (d, J = 4.9 Hz, 1H), 7.56 (br d, J = 9.9 Hz, 1H), 7.28-7.11 (m, 2H), 6.89-6.76 (m,1H),6.71-6.55(m,2H),6.28(br dd,J＝1.8,16.8Hz,1H),5.82(br d,J＝9.9Hz,1H),4.99-4.90(m,1H ),4.72-4.38(m,2H),4.27-4.10(m,1H),3.75-3.58(m,3H),3.47(br d,J＝11.9Hz,2H),3.25(br s,2H), 2.99(br s,1H),2.67(td,J＝6.7,13.5Hz,1H),2.05(s,3H),1.92-1.64(m,5H),1.14(dd,J＝6.8,15.9Hz,6H).

MS (ESI) m/z (M+H) ⁺ = 662.4.

SFC retention time 2.242 min

Separation conditions: Chromatographic column: Chiralpak IC-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 50%-50%; flow rate: 2.5 mL/min.

Compound 35A-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.40 (d, J = 4.9 Hz, 1H), 7.55 (br d, J = 9.3 Hz, 1H), 7.26-7.12 (m, 2H), 6.83 (br dd,J＝10.4,16.1Hz,1H),6.71-6.56(m,2H),6.27(br dd,J＝1.8,16.8Hz,1H),5.81(br d,J＝10.4Hz,1H),5.00-4.90(m,1H),4.71-4.42(m,2H),4.25-4.10(m,1H),3.82-3.62(m,3H),3.54-3.40( m,2H),3.29-3.14(m,2H),3.00(br s,1H),2.76-2.66(m,1H),2.03(s,3H),1.92-1.68(m,5H),1.25-0.96 (m,6H).

MS (ESI) m/z (M+H) ⁺ = 662.4.

SFC retention time: 2.800 min.

Separation conditions: Chromatographic column: Chiralpak IC-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 50%-50%; flow rate: 2.5 mL/min.

Step 5: Preparation of compounds 35B-1 and 35B-2

The diastereoisomer compound 35B was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 μm); mobile phase: [CO ₂ -methanol (0.1% ammonia water)]; methanol%: 40%). After concentration, compound 35B-1 and compound 35B-2 were obtained.

Compound 35B-1:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.41 (d, J = 4.9 Hz, 1H), 7.55 (br d, J = 9.3 Hz, 1H), 7.34-7.12 (m, 2H), 6.82 (br d,J＝13.7Hz,1H),6.69-6.55(m,2H),6.28(dd,J＝1.8,16.8Hz,1H),5.81(br d,J＝9.9Hz,1H),4.96(br s ,1H),4.71-4.43(m,2H),4.27-4.08(m,1H),3.82-3.57(m,3H),3.48(br d,J＝12.6Hz,2H),3.27-3.30(m, 2H),3.02(br d,J＝10.4Hz,1H),2.81-2.62(m,1H),2.03(s,3H),1.85-1.67(m,5H),1.13(dd,J＝6.8,15.7Hz,6H).

MS (ESI) m/z (M+H) ⁺ = 662.4.

SFC retention time: 1.850 min.

Separation conditions: Chromatographic column: Chiralpak IC-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -methanol (0.05% DEA); methanol: 40%-40%; flow rate: 2.8 mL/min.

Compound 35B-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.30 (d, J = 4.9 Hz, 1H), 7.45 (br d, J = 9.3 Hz, 1H), 7.16-7.01 (m, 2H), 6.74 (br s,1H),6.61-6.46(m,2H),6.17(br dd,J＝1.5,16.8Hz,1H),5.72(br s,1H),4.88-4.81(m,1H),4.59-4.30( m,2H),4.16-4.00(m,1H),3.63-3.46(m,3H),3.38(br d,J＝11.9Hz,2H),3.15(br s,2H),2.88(br s,1H),2.56(td,J=6.6,13.5Hz,1H),1.95(s,3H),1.81-1.55(m,5H),1.11-0.89(m,6H).

MS (ESI) m/z (M+H) ⁺ = 662.4.

SFC retention time: 2.290 min.

Separation conditions: Chromatographic column: Chiralpak IC-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -methanol (0.05% DEA); isopropanol: 40%-40%; flow rate: 2.8 mL/min.

Example 36: Preparation of Compound 36

Step 1: Preparation of compound 36-2

Compound 16-3 (100 mg, 150.66 μmol) was dissolved in N, N-dimethylformamide (2 mL), sodium hydride (40 mg, 1.00 mmol, 60%) was added thereto, and the reaction was stirred at room temperature (25°C) for 0.5 h, and compound 36-1 (100 mg, 418.02 μmol) was added thereto, and the reaction was stirred at room temperature (25°C) for 1 h. The reaction solution was quenched with 3 drops of saturated ammonium chloride solution, diluted with ethyl acetate (30 mL), washed with water (10 mL) and saturated sodium chloride solution (10 mL) in sequence, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-7%) to obtain compound 36-2.

MS (ESI) m/z (M+H) ⁺ = 822.4.

Step 2: Preparation of compound 36-3

Compound 36-2 (180 mg, 218.97 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (274.28 mg, 1.09 mmol, 105.49 uL) was added thereto, and the reaction was stirred at room temperature (20°C) for 5 h. The reaction solution was quenched with methanol (10 mL) and stirred for 10 min. The system was concentrated to obtain compound 36-3, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 594.4.

Step 3: Preparation of compounds 36A and 36B

Compound 36-3 (150 mg, 222.37 μmol, HBr) was dissolved in tetrahydrofuran (2 mL) and an aqueous solution (2.5 mL) of sodium bicarbonate (5.40 g, 64.28 mmol), and a tetrahydrofuran solution (0.5 mL) of acrylic anhydride (28.04 mg, 222.37 μmol) was added dropwise. After the addition was completed, the system was stirred at room temperature (20°C) for 2 h. Methanol (1 mL) and an aqueous solution of potassium carbonate (2M, 1 mL) were added to the system, and the system was stirred at room temperature (20°C) for 1.5 h. Water (10 mL) was added to the system for dilution, and the pH was adjusted to ~6 with 1N HC, extracted with ethyl acetate (20 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-performance preparative liquid phase (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30mm*3μm, mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile 43%-73% 9min) to obtain compounds 36A and 36B.

Compound 36A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.40 (d, J = 4.9 Hz, 1H), 7.55 (br d, J = 7.9 Hz, 1H), 7.27-7.14 (m, 2H), 6.83 (dd ,J＝10.6,16.8Hz,1H),6.71-6.55(m,2H),6.27(dd,J＝1.8,16.8Hz,1H),5.81(br d,J＝12.1Hz,1H),5.00-4.92 (m,1H),4.68-4.45(m,2H),4.25-4.06(m,1H),3.86(br dd,J＝5.1,14.3Hz,1H),3.74(dt,J＝6.2,11.6Hz,4H),3.57-3.40(m,2H),3.15-2.99(m,1H),2.80-2.60(m, 1H),2.05(d,J=7.5Hz,3H),1.81-1.65(m,3H),1.21-1.05(m,6H).

MS (ESI) m/z (M+H) ⁺ = 648.4.

LCMS retention time 1.579 & 1.635 min.

Separation conditions: Chromatographic column: XBridge C18 3.5μm 2.1*30mm; Column temperature: 50℃; Mobile phase: Water (0.8mL/4L NH ₃ ·H ₂ O)-acetonitrile; Acetonitrile: 10%-80% 2min, 80% 0.48min; Flow rate: 1mL/min.

Compound 36B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.41 (d, J = 5.1Hz, 1H), 7.55 (br d, J = 7.3Hz, 1H), 7.31-7.13 (m, 2H), 6.84 (br dd,J＝10.7,16.9Hz,1H),6.71-6.53(m,2H),6.33-6.21(m,1H),5.82(br s,1H),5.01-4.93(m,1H),4.68-4.45 (m,2H),4.16(br d,J＝13.7Hz,1H),3.85(br d,J＝14.3Hz,1H),3.80-3.64(m,4H),3.55-3.40(m,2H),3.19-2.99(m,1H),2.78-2.56(m,1H),2.05(d, J＝15.7Hz,3H),1.81-1.64(m,3H),1.22-1.05(m,6H).

MS (ESI) m/z (M+H) ⁺ = 648.4.

LCMS retention time 1.613 & 1.653 min.

Separation conditions: Chromatographic column: XBridge C18 3.5μm 2.1*30mm; Column temperature: 50℃; Mobile phase: Water (0.8mL/4L NH ₃ ·H ₂ O)-acetonitrile; Acetonitrile: 10%-80% 2min, 80% 0.48min; Flow rate: 1mL/min.

Step 4: Preparation of compounds 36A-1 and 36A-2

The diastereoisomer compound 36A was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase: [CO ₂ -isopropanol (0.1% ammonia water)]; isopropanol%: 30%). After concentration, compound 36A-1 and compound 36A-2 were obtained.

Compound 36A-1:

¹ H NMR (400MHz, Methanol-d ₄ ) δ = 8.41 (d, J = 5.0Hz, 1H), 7.55 (br d, J = 8.3Hz, 1H), 7.27-7.16 (m, 2H), 6.84 (dd ,J＝10.7,16.7Hz,1H),6.71-6.56(m,2H),6.27(dd,J＝1.8,16.7Hz,1H),5.81(br d,J＝9.7Hz,1H),5.00-4.92(m,1H),4.68-4.47(m,2H),4.33-4.06(m,1H),3.91-3.64(m,5H),3.55-3.38( m,2H),3.14-2.99(m,1H),2.79-2.68(m,1H),2.04(s,3H),1.82-1.66(m,3H),1.21-1.04(m,6H).

MS (ESI) m/z (M+H) ⁺ = 648.2.

HPLC retention time 7.86min

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min SFC retention time 1.604min

Separation conditions: Chromatographic column: Chiralpak AD-3 50*4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; flow rate: 4mL/min.

Compound 36A-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ = 8.40 (d, J = 5.0Hz, 1H), 7.55 (br d, J = 9.9Hz, 1H), 7.26-7.17 (m, 1H), 7.16 (s ,1H),6.83(dd,J＝10.7,16.7Hz,1H),6.68-6.57(m,2H),6.27(dd,J＝1.7,16.7Hz,1H),5.81(br d,J＝11.1Hz ,1H),5.00-4.91(m,1H),4.75-4.40(m,2H),4.24-4.06(m,1H),3.93-3.74(m,4H),3.52-3.39(m,2H),3.05 (br d,J＝12.0Hz,1H),2.65(td,J＝6.8,13.6Hz,1H),2.10-2.01(m,3H),1.81-1.68(m,3H),1.13(dd,J＝6.8, 17.0Hz,6H).

MS (ESI) m/z (M+H) ⁺ = 648.2.

HPLC retention time: 7.96 min

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min SFC retention time 1.705min

Separation conditions: Chromatographic column: Chiralpak AD-3 50*4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; flow rate: 4mL/min.

Step 5: Preparation of compounds 36B-1 and 36B-2

The diastereoisomer compound 36B was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD-H (250mm*30mm, 10μm); mobile phase: [CO ₂ -isopropanol (0.1% ammonia water)]; isopropanol%: 30%). After concentration, compound 36B-1 and compound 36B-2 were obtained.

Compound 36B-1:

¹ H NMR (400MHz, Methanol-d ₄ ) δ = 8.41 (d, J = 5.0Hz, 1H), 7.55 (br d, J = 9.3Hz, 1H), 7.27-7.15 (m, 2H), 6.83 (br dd,J＝10.8,16.5Hz,1H),6.68-6.55(m,2H),6.27(dd,J＝1.5,16.8Hz,1H),5.80(br d,J＝9.1Hz,1H),5.00-4.92(m,1H),4.67-4.49(m,2H),4.25-4.06(m,1H),3.90-3.65(m,5H),3.55-3.39( m,2H),3.16-2.99(m,1H),2.79-2.67(m,1H),2.03(s,3H),1.80-1.66(m,3H),1.13(dd,J＝6.7,18.3Hz, 6H).

MS (ESI) m/z (M+H) ⁺ = 648.1.

HPLC retention time: 8.16 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min SFC retention time 1.603min

Separation conditions: Chromatographic column: Chiralpak AD-3 50*4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; flow rate: 4mL/min.

Compound 36B-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ = 8.40 (d, J = 4.9Hz, 1H), 7.55 (br d, J = 10.3Hz, 1H), 7.26-7.15 (m, 2H), 6.83 (dd ,J＝10.7,16.7Hz,1H),6.71-6.56(m,2H),6.27(dd,J＝1.8,16.7Hz,1H),5.81(br d,J＝10.1Hz,1H),4.95(br s,1H),4.74-4.45(m,2H),4.32-4.04(m,1H),3.92-3.62(m,5H),3.56-3.40(m,2H),3.03(br s,1H),2.71-2.58(m,1H),2.07(s,3H),1.82-1.66(m,3H),1.19-1.02(m,6H).

MS (ESI) m/z (M+H) ⁺ = 648.1.

HPLC retention time: 8.11 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min SFC retention time 1.730min.

Separation conditions: Chromatographic column: Chiralpak AD-3 50*4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; flow rate: 4mL/min.

Example 37: Preparation of Compound 37

Step 1: Preparation of compound 37-2

Triphenylphosphine (2.18 g, 8.32 mmol) was dissolved in anhydrous dichloromethane (20 mL), and iodine (2.11 g, 8.32 mmol) and 4-dimethylaminopyridine (271.12 mg, 2.22 mmol) were added thereto. After the addition was completed, the reaction was stirred at room temperature (25 ° C) for 5 min, and compound 37-1 (0.5 g, 5.55 mmol) was added thereto, and the reaction was stirred at room temperature (25 ° C) for 12 h. The reaction solution was quenched with saturated sodium thiosulfate solution, extracted with dichloromethane (20 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by medium pressure column chromatography (methanol/dichloromethane (v/v) = 0-10%) to obtain compound 37-2.

¹ H NMR(400MHz, DMSO-d ₆ )4.63(d,J＝4.8Hz,1H),3.69-3.57(m,1H),3.32-3.23(m,2H),1.87-1.76(m,2H), 1.07(d,J＝6.0Hz,3H).

Step 2: Preparation of compound 37-3

Compound 37-2 (1 g, 5.00 mmol) was dissolved in anhydrous dichloromethane (20 mL). Imidazole (408.46 mg, 6.00 mmol) and tert-butyldimethylsilyl chloride (904.33 mg, 6.00 mmol, 735.23 uL) were added sequentially at 0°C. After the addition, the reaction mixture was heated to room temperature (25°C) and stirred for 12 h. The reaction solution was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-10%) to obtain compound 37-3.

¹ H NMR (400MHz, DMSO-d ₆ )3.91-3.81(m,1H),3.32-3.17(m,2H),1.89-1.81(m,2H),1.12(d,J＝6.3Hz,3H), 0.87(s,9H),0.08(d,J=6.3Hz,6H).

Step 3: Preparation of compound 37-4

Compound 16-3 (100 mg, 150.66 μmol) was dissolved in N, N-dimethylformamide (2 mL), sodium hydride (31 mg, 775.07 μmol, 60%) was added thereto, and the reaction was stirred at room temperature (25°C) for 0.5 h, and compound 37-3 (140 mg, 445.47 μmol) was added thereto, and the reaction was stirred at room temperature (25°C) for 1 h. The reaction solution was quenched with 3 drops of saturated ammonium chloride solution, diluted with ethyl acetate (30 mL), washed with water (10 mL) and saturated sodium chloride solution (10 mL) in sequence, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-7%) to obtain compound 37-4.

MS (ESI) m/z (M+H) ⁺ = 850.2.

Step 4: Preparation of compound 37-5

Compound 37-4 (85 mg, 99.99 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (260 mg, 1.04 mmol, 0.1 mL) was added thereto, and the reaction was stirred at room temperature (20 ° C) for 6 h. The reaction solution was quenched with methanol (5 mL) and stirred for 10 min. The system was diluted with dichloromethane (30 mL), washed with saturated sodium bicarbonate aqueous solution (30 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 37-5, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 622.1.

Step 5: Preparation of compounds 37A and 37B

Compound 37-5 (70 mg, 112.60 μmol) was dissolved in tetrahydrofuran (1.5 mL) and an aqueous solution (1.62 mL) of sodium bicarbonate (3.49 g, 41.53 mmol), and a tetrahydrofuran solution (0.5 mL) of acrylic anhydride (28.04 mg, 222.37 μmol) was added dropwise. After the addition was completed, the system was stirred at room temperature (20°C) for 2 h. Methanol (1 mL) and an aqueous potassium carbonate solution (2M, 1 mL) were added to the system, and the system was stirred at room temperature (20°C) for 1.5 h. Water (10 mL) was added to the system for dilution, and the pH was adjusted to ~6 with 1N HC, extracted with ethyl acetate (20 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-performance preparative liquid phase (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30mm*3μm, mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile 43%-73% 9min) to obtain compounds 37A and 37B.

Compound 37A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.41 (d, J = 5.0Hz, 1H), 7.56 (br d, J = 8.5Hz, 1H), 7.28-7.14 (m, 2H), 6.84 (br dd,J＝10.7,16.6Hz,1H),6.71-6.56(m,2H),6.28(br d,J＝17.3Hz,1H),5.82(br d,J＝10.0Hz,1H),5.00-4.60(m,4H),4.27-4.04(m,1H),3.98-3.66(m,2H),3.60-3.43(m,2H),3.27-2.90( m,2H),2.83-2.59(m,1H),2.11-1.99(m,3H),1.89-1.58(m,5H),1.24-1.05(m,9H).

MS (ESI) m/z (M+H) ⁺ = 676.3.

LCMS retention time 2.927 min.

Separation conditions: Chromatographic column: Xtimate C18 2.1*30mm, 3μm; Column temperature: 50℃; Mobile phase: Water (1.5mL/4L trifluoroacetic acid)-Acetonitrile (0.75mL/4L trifluoroacetic acid); Acetonitrile: 10%-80% 6min, 80% 0.5min; Flow rate: 0.8mL/min.

Compound 37B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.41 (d, J = 4.8Hz, 1H), 7.56 (br d, J = 9.7Hz, 1H), 7.27-7.16 (m, 2H), 6.84 (br dd,J＝10.8,16.6Hz,1H),6.70-6.57(m,2H),6.28(br d,J＝16.6Hz,1H),5.82(br s,1H),4.60(br s,3H),4.30-4.06(m,1H),3.98-3.65(m,2H),3.57-3.40(m,2H),3.25-2.92(m,3H),2.78-2.59(m,1H), 2.10-1.99(m,3H),1.90-1.52(m,5H),1.23-1.01(m,9H).

MS (ESI) m/z (M+H) ⁺ = 676.3.

LCMS retention time 3.109 min.

Separation conditions: Chromatographic column: Xtimate C18 2.1*30mm, 3μm; Column temperature: 50℃; Mobile phase: Water (1.5mL/4L trifluoroacetic acid)-Acetonitrile (0.75mL/4L trifluoroacetic acid); Acetonitrile: 10%-80% 6min, 80% 0.5min; Flow rate: 0.8mL/min.

Example 38: Preparation of Compound 38

Step 1: Preparation of compound 38-1

Compound 16-3 (150 mg, 226.00 μmol) was dissolved in N,N-dimethylformamide (2 mL), and sodium hydride (50 mg, 1.25 mmol, 60%) was added thereto. After the addition was completed, the reaction was stirred at room temperature (25°C) for 0.5 h, and methyl bromoacetate (100 mg, 653.70 μmol, 61.73 uL) was added thereto, and the reaction was stirred at room temperature (25°C) for 1 h. The reaction solution was quenched with 3 drops of saturated ammonium chloride solution, poured into ice water, precipitated, filtered, and the filter cake was collected and dried to obtain compound 38-1, which was directly used in the next step without further purification.

MS (ESI) m/z (M+Na) ⁺ = 758.3.

Step 2: Preparation of compound 38-2

Compound 38-1 (160 mg, 217.45 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (160 mg, 217.45 μmol) was added thereto, and the reaction was stirred at room temperature (20°C) for 6 h. The reaction solution was quenched with methanol (5 mL) and stirred for 10 min. The system was concentrated to obtain compound 38-2, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 622.1.

Step 3: Preparation of compounds 38A and 38B

Compound 38-2 (200 mg, 284.67 μmol, hydrobromide) was dissolved in tetrahydrofuran (2 mL) and an aqueous solution (2 mL) of sodium bicarbonate (4.32 g, 51.42 mmol), and a tetrahydrofuran solution (1 mL) of acrylic anhydride (70 mg, 555.11 μmol) was added dropwise. After the addition was completed, the system was stirred at room temperature (20°C) for 1 h. Methanol (1 mL) and an aqueous potassium carbonate solution (2M, 1 mL) were added to the system, and the system was stirred at room temperature (20°C) for 1.5 h. Water (10 mL) was added to the system for dilution, and the pH was adjusted to ~6 with 1N HC. The system was extracted with ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-performance preparative liquid phase (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30mm*3μm, mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile 50%-80% 9min) to obtain compounds 38A and 38B.

Compound 38A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.40 (d, J = 4.9 Hz, 1H), 7.58 (br d, J = 8.6 Hz, 1H), 7.27-7.14 (m, 2H), 6.89-6.75 (m,1H),6.72-6.58(m,2H),6.27(br dd,J＝1.2,16.9Hz,1H),5.81(br d,J＝10.8Hz,1H),5.00(br d,J＝ 16.8Hz,1H),4.67-4.50(m,2H),4.27-4.04(m,2H),3.92-3.58(m,5H),3.55-3.45(m,1H),3.38(br dd,J＝4.5,12.5Hz,1H),3.28-3.09(m,2H),2.71-2.58(m,1H),2.01(br d,J＝12.6Hz,3H),1.84-1.63(m,3H ),1.23-0.93(m,6H).

MS (ESI) m/z (M+H) ⁺ = 676.2.

Compound 38B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.40 (d, J = 4.9 Hz, 1H), 7.58 (br d, J = 8.6 Hz, 1H), 7.27-7.14 (m, 2H), 6.89-6.75 (m,1H),6.72-6.58(m,2H),6.27(br dd,J＝1.2,16.9Hz,1H),5.81(br d,J＝10.8Hz,1H),5.00(br d,J＝ 16.8Hz,1H),4.67-4.50(m,2H),4.27-4.04(m,2H),3.92-3.58(m,5H),3.55-3.45(m,1H),3.38(br dd,J＝4.5,12.5Hz,1H),3.28-3.09(m,2H),2.71-2.58(m,1H),2.01(br d,J＝12.6Hz,3H),1.84-1.63(m,3H ),1.23-0.93(m,6H).

MS (ESI) m/z (M+H) ⁺ = 676.2.

Step 4: Preparation of compounds 38A-1 and 38A-2

The diastereoisomer compound 38A was purified by SFC (separation conditions: chromatographic column DAICEL CHIRALPAK IG (250 mm*30 mm, 10 μm); mobile phase: [CO ₂ -isopropanol (0.1% ammonia water)]; isopropanol%: 35%). After concentration, compound 38A-1 and compound 38A-2 were obtained.

Compound 38A-1:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.39 (d, J = 5.1 Hz, 1H), 7.57 (br d, J = 8.8 Hz, 1H), 7.27-7.14 (m, 2H), 6.89-6.77 (m,1H),6.70-6.56(m,2H),6.26(br dd,J＝1.8,16.8Hz,1H),5.81(br d,J＝10.4Hz,1H),5.08-4.96(m,1H ),4.61(br d,J＝13.7Hz,1H),4.52(br s,1H),4.29-4.07(m,2H),3.86-3.76(m,1H),3.73-3.58(m,3H), 3.50(br d,J＝17.2Hz,1H),3.37(br d,J＝12.8Hz,1H),3.27-3.12(m,2H),2.66-2.56(m,1H),2.01(s,3H),1.85- 1.65(m,3H),1.12(br t,J＝7.1Hz,6H).

MS (ESI) m/z (M+H) ⁺ = 676.2.

SFC retention time: 5.434 min.

Separation conditions: Chromatographic column: ChiralPak IC-3 150×4.6 mm ID, 3 μm; column temperature: 40°C; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% 5.5 min, 40% 3 min, 5% 1.5 min; flow rate: 2.5 mL/min.

Compound 38A-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.41 (d, J = 5.1 Hz, 1H), 7.58 (br d, J = 8.2 Hz, 1H), 7.32-7.14 (m, 2H), 6.91-6.76 (m,1H),6.70-6.55(m,2H),6.27(br d,J＝17.0Hz,1H),5.81(dd,J＝1.9,10.7Hz,1H),5.30-5.16(m,1H) ,4.70-4.40(m,2H),4.20-4.02(m,2H),3.90-3.69(m,2H),3.65(s,3H),3.56-3.44(m,1H),3.38(br d,J＝13.0Hz,1H),3.23(br d,J＝13.5Hz,1H),2.73(br s,1H),2.02(s,3H),1.79-1.66(m,3H),1.18-1.02 (m,6H).

MS (ESI) m/z (M+H) ⁺ = 676.2.

SFC retention time: 5.906 min.

Separation conditions: Chromatographic column: ChiralPak IC-3 150×4.6 mm ID, 3 μm; column temperature: 40°C; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% 5.5 min, 40% 3 min, 5% 1.5 min; flow rate: 2.5 mL/min.

Step 5: Preparation of compounds 38B-1 and 38B-2

The diastereoisomer compound 38B was purified by SFC (separation conditions: chromatographic column DAICEL CHIRALPAK IC (250mm*30mm, 5μm); mobile phase: [CO ₂ -ethanol (0.1% ammonia water)]; isopropanol%: 35%). After concentration, compound 38B-1 and compound 38B-2 were obtained.

Compound 38B-1:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.40 (d, J = 4.9 Hz, 1H), 7.58 (br d, J = 9.5 Hz, 1H), 7.27-7.17 (m, 2H), 6.88-6.77 (m,1H),6.67-6.58(m,2H),6.27(br d,J＝15.2Hz,1H),5.81(br d,J＝10.8Hz,1H),5.29-5.15(m,1H), 4.64-4.52(m,2H),4.20-4.03(m,2H),3.90-3.78(m,1H),3.65(s,3H),3.58-3.47(m,1H),3.40(br d,J＝12.3Hz,1H),3.24(br d,J＝13.2Hz,2H),2.71(br s,1H),2.00(s,3H),1.82-1.67(m,3H),1.10(br dd,J＝3.1,6.6Hz,6H).

MS (ESI) m/z (M+H) ⁺ = 676.2.

SFC retention time: 5.362 min.

Separation conditions: Chromatographic column: ChiralPak IG-3 100×4.6 mm ID, 3 μm; column temperature: 40°C; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% 5.5 min, 40% 3 min, 5% 1.5 min; flow rate: 2.5 mL/min.

Compound 38B-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.39 (d, J = 5.1 Hz, 1H), 7.57 (br d, J = 9.5 Hz, 1H), 7.24-7.15 (m, 2H), 6.88-6.77 (m,1H),6.70-6.57(m,2H),6.26(dd,J＝1.8,16.8Hz,1H),5.81(br d,J＝10.8Hz,1H),5.00(br d,J＝16.5 Hz,1H),4.65-4.48(m,2H),4.31-4.06(m,2H),3.86-3.67(m,2H),3.64(s,3H),3.56-3.44(m,1H),3.38( br d,J＝12.8Hz,1H),3.26-3.09(m,1H),2.61(td,J＝6.8,13.5Hz,1H),2.07-1.99(m,3H),1.79-1.67(m,3H) ,1.17-1.10(m,3H),1.09-1.01(m,3H).

MS (ESI) m/z (M+H) ⁺ = 676.2.

SFC retention time: 5.897 min.

Separation conditions: Chromatographic column: ChiralPak IG-3 100×4.6 mm ID, 3 μm; column temperature: 40°C; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% 5.5 min, 40% 3 min, 5% 1.5 min; flow rate: 2.5 mL/min.

Example 39: Preparation of Compound 39

Step 1: Preparation of compounds 39A and 39B

The mixture of compounds 38A and 38B (50 mg, 74.00 μmol) was dissolved in a mixed solvent of methanol (1 mL) and water (1 mL), and lithium hydroxide (20 mg, 476.60 μmol) was added thereto. After the addition, the system was stirred at room temperature (20°C) for 2 h. Water (5 mL) was added to dilute the system, and the pH was adjusted to ~5 with 1N HC. It was extracted with ethyl acetate (10 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by high-efficiency preparative liquid phase purification (separation conditions: chromatographic column Phenomenex Gemini-

NX 80*30mm*3μm, mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile 10%-80% 9min) to obtain compounds 39A and 39B.

Compound 39A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.39 (br d, J = 4.4Hz, 1H), 7.56 (br d, J = 8.2Hz, 1H), 7.21 (br d, J = 4.2Hz, 2H ),6.82(br d,J＝8.8Hz,1H),6.72-6.51(m,1H),6.27(br d,J＝16.8Hz,1H),5.80(br d,J＝10.1Hz,1H), 5.01-4.96(m,1H),4.70-4.37(m,2H),4.26-3.97(m,2H),3.93-3.66(m,2H),3.48(br s,1H),3.22(br d,J＝13.9Hz,2H),2.81-2.47(m,2H),2.02(br d,J＝9.5Hz,3H),1.87-1.49(m,3H),1.39-0.78(m,6H).

MS (ESI) m/z (M+H) ⁺ = 662.2.

Compound 39B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.39 (d, J = 5.1 Hz, 1H), 7.56 (br d, J = 9.0 Hz, 1H), 7.27-7.14 (m, 2H), 6.81 (br d,J＝10.4Hz,1H),6.69-6.52(m,2H),6.27(br d,J＝16.8Hz,1H),5.80(br d,J＝10.6Hz,1H),5.30-5.06(m,1H),4.66-4.48(m,1H),4.25-3.86(m,2H),3.84-3.56(m,2H),3.55-3.43( m,1H),3.37-3.34(m,1H),3.29-3.14(m,2H),2.76-2.59(m,1H),2.02(br d,J＝19.6Hz,3H),1.90-1.58(m ,3H),1.19-1.02(m,6H).

MS (ESI) m/z (M+H) ⁺ = 662.2.

Step 2: Preparation of compounds 39A-1 and 39A-2

The diastereoisomer compound 39A was purified by SFC (separation conditions: chromatographic column DAICEL CHIRALPAK IC (250 mm*30 mm, 5 μm); mobile phase: [CO ₂ -methanol (0.1% ammonia water)]; methanol%: 35%). After concentration, compound 39A-1 and compound 39A-2 were obtained.

Compound 39A-1:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.38 (d, J = 4.9 Hz, 1H), 7.57 (br s, 1H), 7.25-7.15 (m, 2H), 6.83 (br s, 1H), 6.67-6.54(m,2H),6.26(br d,J＝17.4Hz,1H),5.80(br d,J＝11.0Hz,1H),5.01-4.93(m,1H),4.69-4.39(m, 2H),4.21-3.94(m,2H),3.89-3.66(m,2H),3.49(br s,1H),3.15(br s,2H),2.62(br s,1H),2.04(s,3H),1.81-1.67(m,3H),1.15-1.09(m,6H).

MS (ESI) m/z (M+H) ⁺ = 662.2.

SFC retention time: 5.408 min.

Separation conditions: Chromatographic column: ChiralPak IC-3 150×4.6 mm ID, 3 μm; column temperature: 40° C.; mobile phase: CO ₂ -methanol (0.05% DEA); methanol: 5%-40% 5.5 min, 40% 3 min, 5% 1.5 min; flow rate: 2.5 mL/min.

Compound 39A-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.39 (br d, J = 4.9 Hz, 1H), 7.58 ( br s, 1H), 7.20 ( br d, J = 8.4 Hz, 2H), 6.83 ( br s,1H),6.71-6.56(m,2H),6.27(br d,J＝16.8Hz,1H),5.81(br d,J＝10.1Hz,1H),5.14(br s,1H),4.69- 4.46(m,2H),4.05(br s,2H),3.82(br s,1H),3.69(br d,J＝5.3Hz,1H),3.48(br s,1H),3.14(br s,2H ),2.74(br s,1H),2.01(s,3H),1.84-1.67(m,3H),1.25-1.03(m,6H).

MS (ESI) m/z (M+H) ⁺ = 662.2.

SFC retention time: 5.896 min.

Separation conditions: Chromatographic column: ChiralPak IC-3 150×4.6 mm ID, 3 μm; column temperature: 40° C.; mobile phase: CO ₂ -methanol (0.05% DEA); methanol: 5%-40% 5.5 min, 40% 3 min, 5% 1.5 min; flow rate: 2.5 mL/min.

Example 40: Preparation of Compound 40

Step 1: Preparation of compound 40-1

Compound 21-2 (110 mg, 162.31 μmol) was dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (89.73 mg, 649.24 μmol), compound 36-1 (116.49 mg, 486.93 μmol) and potassium iodide (26.94 mg, 162.31 μmol) were added thereto. After the addition, the system was heated to 100°C and stirred for 16 hours. After the reaction was cooled to room temperature (25°C), water (10 mL) and ethyl acetate (10 mL x 2) were added thereto for separation and extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 40-1, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 836.3.

Step 2: Preparation of compound 40-2

Compound 40-1 (170 mg, 203.34 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (260 mg, 1.04 mmol, 0.1 mL) was added thereto, and the reaction was stirred at room temperature (20 ° C) for 2 h. The reaction solution was quenched with methanol (2 mL) and stirred for 10 min. After adding dichloromethane (30 mL) to the system, it was washed with saturated sodium bicarbonate aqueous solution (30 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude product 40-2, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 608.1.

Step 3: Preparation of compounds 40A and 40B

Compound 40-2 (120.00 mg, 197.49 μmol) was dissolved in tetrahydrofuran (2 mL) and an aqueous solution (2 mL) of sodium bicarbonate (4.32 g, 51.42 mmol), and acrylic anhydride (24.91 mg, 197.49 μmol) was added dropwise. After the addition was completed, the system was stirred at room temperature (25°C) for 0.5 h. Methanol (2 mL) and a saturated aqueous potassium carbonate solution (2 mL) were added to the system, and the system was stirred at room temperature (20°C) for 1 h. Water (10 mL) was added to the system for dilution, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid phase (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30mm*3μm, mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; acetonitrile 32%-62% 9min) to obtain compounds 40A and 40B.

Compound 40A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 5.1 Hz, 1H), 7.69 (br d, J = 9.0 Hz, 1H), 7.34-7.04 (m, 3H), 6.66 (td ,J＝9.4,18.7Hz,2H),6.23(br d,J＝16.1Hz,1H),5.81(br d,J＝10.4Hz,1H),4.97-4.94(m,1H),4.68-4.33( m,3H),3.91(br d,J＝11.0Hz,1H),3.64(brd,J＝5.5Hz,2H),3.48(br s,1H),3.23-2.95(m,2H),2.55(s,1H),2.21-1.97(m,3H),1.76-1.65(m,3H),1.10(br dd,J＝6.6,17.2Hz ,6H).

MS (ESI) m/z (M+H) ⁺ = 662.3.

SFC retention time: 5.835 min.

Separation conditions: Chromatographic column: Cellulose 2 150×4.6mm ID, 5μm; Column temperature: 35°C; Mobile phase: CO ₂ -methanol (0.05% DEA)-methanol%: 5%-40% 5min, 40% 2.5min, 5% 2.5min; Flow rate: 2.5mL/min.

Compound 40B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 5.1 Hz, 1H), 7.68 (br d, J = 9.3 Hz, 1H), 7.33-7.03 (m, 3H), 6.75-6.53 (m,2H),6.32-6.14(m,1H),5.87-5.71(m,1H),5.00-4.91(m,1H),4.80-4.30(m,2H),4.00-3.51(m,4H) ,3.26-2.89(m,3H),2.61-2.44(m,1H),2.26-1.90(m,3H),1.79-1.56(m,3H),1.26-0.85(m,6H).

MS (ESI) m/z (M+H) ⁺ = 662.3.

SFC retention time: 6.379 min.

Separation conditions: Chromatographic column: Cellulose 2 150×4.6mm ID, 5μm; Column temperature: 35°C; Mobile phase: CO ₂ -methanol (0.05% DEA)-methanol%: 5%-40% 5min, 40% 2.5min, 5% 2.5min; Flow rate: 2.5mL/min.

Step 4: Preparation of Compounds 40A-1 and 40A-2

The diastereoisomer compound 40A was purified by SFC (separation conditions: chromatographic column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 μm); mobile phase: [CO ₂ -methanol (0.1% ammonia water)]; methanol%: 40%). After concentration, compound 40A-1 and compound 40A-2 were obtained.

Compound 40A-1:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 5.0 Hz, 1H), 7.69 (br d, J = 9.2 Hz, 1H), 7.29-7.20 (m, 2H), 7.13 (dd ,J＝10.7,16.9Hz,1H),6.73-6.59(m,2H),6.31-6.18(m,1H),5.84-5.74(m,1H),4.97-4.94(m,1H),4.79-4.59 (m,2H),4.53-4. 27(m,2H),4.01-3.86(m,2H),3.73-3.55(m,2H),3.21-3.12(m,1H),3.00(quin,J＝6.7Hz,1H),1.98(s, 3H),1.75-1.65(m,3H),1.23(d,J＝6.7Hz,3H),1.12(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 662.2.

HPLC retention time: 7.66 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min SFC retention time 4.617min.

Separation conditions: Chromatographic column: ChiralPak IG-3 100×4.6mm ID, 3μm; Column temperature: 40°C; Mobile phase: CO ₂ -ethanol (0.05% DEA)-ethanol%: 5%-40% 5.5min, 40% 3min, 5% 1.5min; Flow rate: 2.5mL/min.

Compound 40A-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ = 8.44 (d, J = 5.0 Hz, 1H), 7.76-7.63 (m, 1H), 7.28-7.19 (m, 2H), 7.12 (dd, J = 10.7 ,16.9Hz,1H),6.70-6.59(m,2H),6.28-6.18(m,1H),5.84-5.73(m,1H),4.94(br s,1H),4.78-4.71(m,1H) ,4.55(br s,1H),4.47-4.39(m,2H),4.01-3.86(m,2H),3.69-3.59(m,2H),3.23-3.06(m,1H),2.55(td,J＝6.7,13.4 Hz,1H),2.18(s,3H),1.75-1.65(m,3H),1.12(d,J＝6.7Hz,3H),1.08(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 662.2.

HPLC retention time: 7.68 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min SFC retention time 4.826min.

Separation conditions: Chromatographic column: ChiralPak IG-3 100×4.6mm ID, 3μm; Column temperature: 40°C; Mobile phase: CO ₂ -ethanol (0.05% DEA)-ethanol%: 5%-40% 5.5min, 40% 3min, 5% 1.5min; Flow rate: 2.5mL/min.

Step 5: Preparation of compounds 40B-1 and 40B-2

The diastereoisomer compound 40B was purified by SFC (separation conditions: chromatographic column: Phenomenex-Cellulose-2 (250mm*30mm, 10μm); mobile phase: [ _CO2 -methanol (0.1% ammonia water)]; methanol%: 40%). After concentration, compound 40B-1 and compound 40B-2 were obtained.

Compound 40B-1:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 5.0 Hz, 1H), 7.68 (br d, J = 9.2 Hz, 1H), 7.29-7.20 (m, 2H), 7.12 (dd ,J＝10.7,16.9Hz,1H),6.72-6.57(m,2H),6.30-6.17(m,1H),5.85-5.74(m,1H),4.92(br s,1H),4.74(br d ,J＝13.1Hz,1H),4.58(br s,1H),4.43(t,J＝5.5Hz,2H),4.04-3.85(m,2H),3.71-3.58(m,2H),3.23-3.06(m,1H),2.59-2.49(m, 1H),2.19(s,3H),1.76-1.66(m,3H),1.12(d,J＝6.7Hz,3H),1.02(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 662.2.

HPLC retention time: 8.02 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min SFC retention time 5.835min.

Separation conditions: Chromatographic column: Cellulose 2 150×4.6mm ID, 5μm; Column temperature: 35°C; Mobile phase: CO ₂ -methanol (0.05% DEA)-methanol%: 5%-40% 5min, 40% 2.5min, 5% 2.5min; Flow rate: 2.5mL/min.

Compound 40B-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.45 (d, J = 5.0 Hz, 1H), 7.68 (br d, J = 9.2 Hz, 1H), 7.30-7.18 (m, 2H), 7.11 (dd ,J＝10.7,16.9Hz,1H),6.71-6.58(m,2H),6.29-6.17(m,1H),5.84-5.73(m,1H),4.92(br s,1H),4.74(br d,J＝12.8Hz,1H),4.52-4.32(m,2H),4.00-3.85(m,2H),3.77-3.42(m,3H),3.20-3.11(m,1H),3.00(td, J＝6.6,13.6Hz,1H),1.98(s,3H),1.75-1.64(m,3H),1.23(d,J＝6.8Hz,3H),1.16(d,J＝6.7Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 662.1.

HPLC retention time: 8.08 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; column temperature: 40℃; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min SFC retention time 6.379min.

Separation conditions: Chromatographic column: Cellulose 2 150×4.6mm ID, 5μm; Column temperature: 35°C; Mobile phase: CO ₂ -methanol (0.05% DEA)-methanol%: 5%-40% 5min, 40% 2.5min, 5% 2.5min; Flow rate: 2.5mL/min.

Example 41: Preparation of Compound 41

Step 1: Preparation of compound 41-2

Compound 21-2 (90 mg, 132.80 μmol) was dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (73.42 mg, 531.20 μmol), compound 41-1 (100.90 mg, 398.40 μmol) and potassium iodide (22.04 mg, 132.80 μmol) were added thereto. After the addition was completed, the system was heated to 100°C and stirred for 16 hours. After the reaction was cooled to room temperature (25°C), water (10 mL) and ethyl acetate (10 mL x 2) were added thereto for separation and extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 41-2, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 850.3.

Step 2: Preparation of compound 41-3

Compound 41-2 (120 mg, 141.17 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (176.83 mg, 705.84 μmol, 68.01 uL) was added thereto, and the reaction was stirred at room temperature (25 ° C) for 2 h. The reaction solution was quenched with methanol (2 mL) and stirred for 10 min. After adding dichloromethane (20 mL) to the system, it was washed with saturated sodium bicarbonate aqueous solution (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude product 41-3, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 622.4.

Step 3: Preparation of compounds 41A and 41B

Compound 41-3 (90 mg, 131.47 μmol) was dissolved in tetrahydrofuran (5 mL) and an aqueous solution of sodium bicarbonate (3.61 g, 42.98 mmol, 1.67 mL), and acrylic anhydride (16.58 mg, 131.47 μmol) was added dropwise. After the addition was completed, the system was stirred at room temperature (25°C) for 0.5 h. Methanol (2 mL) and a saturated aqueous potassium carbonate solution (2 mL) were added to the system, and the system was stirred at room temperature (20°C) for 1 h. Water (10 mL) was added to the system for dilution, and the system was extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-performance preparative liquid phase (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30mm*3μm, mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile 46%-76% 9min) to obtain compounds 41A and 41B.

Compound 41A:

¹ H NMR (400MHz, Methanol-d ₄ )8.45(d,J＝5.1Hz,1H),7.68(br d,J＝9.7Hz,1H),7.32-7.04(m,3H),6.73-6.59(m ,2H),6.29-6.20(m,1H),5.88-5.77(m,1H),4.99-4.95(m,1H),4.75(br d,J＝12.4Hz,1H),4.62(s,2H) ,4.32(br dd,J＝7.3,13.8Hz,1H),4.26-4.15(m,1H),3.93-3.89(m,1H),3.57-3.49(m,2H),3.40-3.36(m,1H),2.61- 2.48(m,1H),2.20(s,3H),1.82(br s,2H),1.75-1.65(m,3H),1.10(dd,J＝6.8,12.8Hz,6H).

MS (ESI) m/z (M+H) ⁺ = 676.3.

HPLC retention time: 3.033 min.

Separation conditions: chromatographic column: Ultimate C18 3*50mm 3μm; column temperature: 50℃; mobile phase: water (1.5mL/4L trifluoroacetic acid solution)-acetonitrile; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 1.2mL/min.

Compound 41B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.45 (br d, J＝4.6Hz, 1H), 7.68 (br d, J＝8.7Hz, 1H), 7.31-7.20 (m, 2H), 7.12 ( br dd,J＝10.7,16.9Hz,1H),6.73-6.59(m,2H),6.32-6.19(m,1H),5.88-5.75(m,1H),4.99-4.93(m,1H),4.80- 4.45(m,2H),4.41-4.04(m,2H),4.02-3.86(m,2H),3.57-3.34(m,3H),3.05-2.87(m,2H),2.60-2.48(m,1H ),2.20(br s,3H),1.76-1.63(m,3H),1.31-1.06(m,6H).

MS (ESI) m/z (M+H) ⁺ = 676.2.

HPLC retention time: 3.277 min.

Separation conditions: Column: Ultimate C18 3*50mm 3μm; Column temperature: 50℃; Mobile phase: water (1.5mL/4L trifluoroacetic acid solution)-acetonitrile; Acetonitrile: 10%-80% 6min, 80% 2min; Flow rate: 1.2mL/min.

Example 42: Preparation of Compound 42

Step 1: Preparation of compound 42-1

Compound 23-3 (80 mg, 112.96 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (211.11 mg, 1.85 mmol, 137.08 uL) was added thereto. After the addition was completed, the system was stirred at room temperature (25° C.) for 3 h. The system was concentrated to obtain compound 42-1, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 608.1.

Step 2: Preparation of compound 42

Compound 42-1 (80 mg, 110.79 μmol, trifluoroacetate) was dissolved in tetrahydrofuran (5 mL) and an aqueous solution of sodium bicarbonate (4.32 g, 51.42 mmol, 2.00 mL), and acrylic anhydride (13.97 mg, 110.79 μmol) was added dropwise. After the addition was completed, the system was reacted at room temperature (25°C) for 0.5 h. After the system was quenched with methanol (2 mL), water (10 mL) was added to the system, and the system was extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid phase (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30mm*3μm, mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile 55%-85% 9min) and then purified by SFC (separation conditions: chromatographic column Phenomenex-Cellulose-2 (250mm*30mm, 10μm), mobile phase: _CO2 -methanol (0.1% ammonia water); methanol 45%) to obtain compounds 42A and 42B.

Compound 42A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.43 (d, J = 5.0 Hz, 1H), 8.02 (s, 1H), 7.49-7.37 (m, 1H), 7.24 (dd, J = 2.7, 4.8 Hz,1H),7.12(dd,J＝10.7,17.0Hz,1H),6.89(dd,J＝4.1,8.5Hz,1H),6.79(t,J＝8.6Hz,1H),6.31-6.18(m ,1H),5.87-5.75(m,1H),4.93(br s,1H),4.78-4.46(m,2H),4.01-3.84(m,2H),3.72(d,J＝16.2Hz,3H),3.43(s,3H),3.04-2.88(m,2H) ,1.98(d,J＝3.5Hz,3H),1.76-1.62(m,3H),1.22(d,J＝6.8Hz,3H),1.13(dd,J＝6.8,10.0Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 662.2.

HPLC retention time: 8.63 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min.

Compound 42B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (d, J = 4.9 Hz, 1H), 8.02 (s, 1H), 7.47-7.39 (m, 1H), 7.27 (d, J = 4.9 Hz, 1H),7.12(dd,J＝10.7,17.0Hz,1H),6.89(t,J＝8.4Hz,1H),6.79(dt,J＝3.2,8.6Hz,1H),6.32-6.17(m,1H ),5.88-5.75(m,1H),4.93(br s,1H),4.80-4.51(m,2H),4.03-3.87(m,2H),3.77-3.66(m,3H),3.45(s,3H),3.03-2.87(m,1H),2.62- 2.51(m,1H),2.25-2.16(m,3H),1.75-1.63(m,3H),1.12(t,J＝6.3Hz,3H),1.04(dd,J＝6.8,12.8Hz,3H) .

MS (ESI) m/z (M+H) ⁺ = 662.2.

HPLC retention time: 8.57 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10min, 80% 5min; flow rate: 1.5mL/min.

Example 43: Preparation of Compound 43

Step 1: Preparation of compound 43-2

Compound 21-2 (200 mg, 295.11 μmol) was dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (163.14 mg, 1.18 mmol), compound 43-1 (239.15 mg, 885.33 μmol) and potassium iodide (48.99 mg, 295.11 μmol) were added thereto. After the addition was completed, the system was heated to 100°C and stirred for 16 hours. After the reaction was cooled to room temperature (25°C), water (10 mL) and ethyl acetate (10 mL x 2) were added thereto for liquid extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by medium pressure column chromatography (methanol/dichloromethane (v/v) = 0-5%) to obtain compound 43-2.

MS (ESI) m/z (M+H) ⁺ = 867.4.

Step 2: Preparation of compound 43-3

Compound 43-2 (140 mg, 161.49 μmol) was dissolved in methanol (2 mL), palladium/carbon (40 mg, 10%) was added, and the reaction was stirred at room temperature (20°C) for 12 h under a hydrogen atmosphere. The system was filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (methanol/dichloromethane (v/v) = 0-5%) to obtain compound 43-3.

MS (ESI) m/z (M+H) ⁺ = 733.1.

Step 3: Preparation of compound 43-4

Compound 43-3 (60 mg, 81.88 μmol) and sodium acetate (70 mg, 853.31 μmol) were dissolved in methanol (2 mL), and formaldehyde (654.00 mg, 8.06 mmol, 0.6 mL, 37% purity) was added thereto, and then a solution of sodium cyanoborohydride (60 mg, 954.78 μmol) in tetrahydrofuran (1 mL) was added thereto. After the addition, the reaction was stirred at room temperature (25°C) for 16 h. Water (10 mL) and ethyl acetate (20 mL) were added to the system for liquid extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (methanol/dichloromethane (v/v) = 0-7%) to obtain compound 43-4.

MS (ESI) m/z (M+H) ⁺ = 747.3.

Step 4: Preparation of compound 43-5

Compound 43-4 (60 mg, 80.34 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (187.61 mg, 1.65 mmol, 121.82 uL) was added thereto. After the addition was completed, the system was stirred at room temperature (25°C) for 3 h. After the system was concentrated, ethyl acetate (20 mL) was added thereto, extracted with water (20 mL x 2), and washed with a saturated sodium bicarbonate aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 43-5, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 647.1.

Step 5: Preparation of compound 43

Compound 43-5 (30 mg, 46.39 μmol) was dissolved in dichloromethane (1 mL), and triethylamine (46.94 mg, 463.89 μmol, 64.57 uL) was added thereto. After the addition, the system was cooled to -40 °C, and a dichloromethane (1 mL) solution of acryloyl chloride (8.40 mg, 92.78 μmol, 7.57 uL) was added dropwise thereto. After the addition, the system was stirred at -40 °C for 0.5 h. After dilution with water (10 mL), the system was extracted with ethyl acetate (10 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30 mm*3 μm, mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; acetonitrile 49%-79% 9 min) to obtain compound 43.

Compound 43:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.45 (d, J = 5.4Hz, 1H), 7.67 (br s, 1H), 7.52-7.40 (m, 1H), 7.32-7.21 (m, 1H) ,7.08(dd,J＝11.1,17.5Hz,1H),6.91(br s,1H),6.84-6.78(m,1H),6.24(br d,J＝15.7Hz,1H),5.81(br d, J＝10.8Hz,1H),5.03-4.94(m,1H),4.73(brd,J＝13.9Hz,1H),4.57(br s,1H),4.08(br s,1H),3.89(br d,J＝12.7Hz,2H),3.79-3.66(m,5H),3.48(br s,1H),3.21-3.03(m,2H),2.47(s,1H),2.35(br s,3H) ,2.24-1.91(m,3H),1.74-1.66(m,3H),1.20-0.96(m,6H).

MS (ESI) m/z (M+H) ⁺ = 701.3.

HPLC retention time 4.305min.

Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; Column temperature: 50°C; Mobile phase: water (0.2mL/1L ammonia)-acetonitrile; Acetonitrile: 10%-80% 6min, 80% 2min; Flow rate: 0.8mL/min

Example 44: Preparation of Compound 44

Step 1: Preparation of compound 44-1

Compound 38-1 (70 mg, 95.14 μmol) was dissolved in ammonia methanol solution (7M, 7.00 mL). Under closed conditions, the system was heated to 100°C and stirred for 6 hours. After the system was cooled to room temperature, it was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (methanol/dichloromethane (v/v) = 0-5%) to obtain compound 44-1.

MS (ESI) m/z (M+H) ⁺ = 721.3.

Step 2: Preparation of compound 44-2

Compound 44-1 (20 mg, 32.22 μmol) was dissolved in a dichloromethane solution of boron tribromide (1 M, 1 mL) and the reaction was stirred at room temperature (25°C) for 2 h. The reaction solution was quenched with methanol (1 mL) at 0°C and the system was concentrated to obtain compound 44-2, which was used directly in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 607.4.

Step 3: Preparation of compounds 44A and 44B

Compound 44-2 (22 mg, 32.00 μmol, HBr salt) was dissolved in tetrahydrofuran (1 mL) and saturated sodium bicarbonate aqueous solution (3.17

g, 37.71mmol, 1.47mL), acrylic anhydride (4.44mg, 35.20μmol) was added dropwise thereto. After the addition was completed, the system was stirred at room temperature (25°C) for 2h. Water (10mL) was added to the system for dilution, and it was extracted with ethyl acetate (10mL x 2). The organic phases were combined and washed with water (10mL x 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30mm*3μm, mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile 33%-63% 9min) to obtain compounds 44A and 44B.

Compound 44A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.42 (br d, J＝5.1Hz, 1H), 7.58 (br s, 1H), 7.29-7.17 (m, 2H), 6.86-6.78 (m, 1H ),6.69-6.57(m,2H),6.27(br d,J＝16.8Hz,1H),5.81(br d,J＝10.6Hz,1H),4.96-4.93(m,1H),4.66-4.49( m,2H),4.19-4.10(m,1H),3.98(br d,J＝17.6Hz,1H),3.72(br s,1H),3.48(br s,1H),3.44-3.34(m,2H ),3.18(br s,2H),2.87-2.77(m,1H),2.68(br s,1H),2.05(br d,J＝11.5Hz,3H),1.80-1.66(m,3H),1.21-0.98(m, 6H).

MS (ESI) m/z (M+H) ⁺ = 661.3.

HPLC retention time 6.71 & 6.79 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min.

Compound 44B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.41 (br d, J＝5.1Hz, 1H), 7.56 (br s, 1H), 7.30-7.16 (m, 2H), 6.82 (br dd, J＝ 10.3,16.9Hz,1H),6.71-6.56(m,2H),6.26(br d,J＝18.5Hz,1H),5.80(br d,J＝10.4Hz,1H),4.96-4.92(m,1H ),4.64-4.47(m,2H),4.14(br d,J＝17.2Hz,2H),3.96(br s,1H),3.71(br s,2H),3.48-3.37(m,2H),3.26-3.07(m,2H),2.89-2.77(m,1H),2.66(br s,1H),2.15-1.95(m,3H),1.84 -1.65(m,3H),1.32-0.99(m,6H).

MS (ESI) m/z (M+H) ⁺ = 661.3.

HPLC retention time 6.90 & 6.97 min.

Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% 10min, 80% 5min; Flow rate: 1.5mL/min.

Example 45: Preparation of Compound 45

Step 1: Preparation of compound 45-1

Compound 4-9 (3.5 g, 9.47 mmol), p-methoxybenzyl chloride (2.96 g, 18.93 mmol, 2.58 mL) and potassium carbonate (3.92 g, 28.40 mmol) were dissolved in N,N-dimethylformamide (30 mL). After the addition, the system was heated to 70 ° C and stirred for 6 hours. After dilution with ethyl acetate (50 mL), the system was washed with saturated brine (50 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 45-1.

MS (ESI) m/z (M+Na) ⁺ = 512.2.

Step 2: Preparation of compound 45-2

At room temperature (20°C), compound 45-1 (4.4 g, 8.98 mmol) was dissolved in toluene (80 mL), and potassium tert-butoxide (1 M, 17.96 mL) was added thereto. After the addition, the system was reacted at room temperature (20°C) for 4 h under a nitrogen atmosphere. 1 M hydrochloric acid was added to the system to quench the reaction, and the system was concentrated and freeze-dried to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-100%) to obtain compound 45-2.

¹ H NMR (400MHz, DMSO-d ₆ ) 12.04 (br s, 1H), 7.88 (d, J = 1.2Hz, 1H), 7.55-7.45 (m, 1H), 7.03-6.79 (m, 6H), 6.07 (s,1H),5.38(br s,2H),3.71-3.59(m,6H).

MS (ESI) m/z (M+Na) ⁺ = 480.1.

Step 3: Preparation of compound 45-3

Compound 45-2 (3.6 g, 7.86 mmol) was dissolved in glacial acetic acid (30 mL). Nitric acid (4.20 g, 66.65 mmol, 3 mL) was added dropwise to the system at room temperature (20 ° C). After the addition was complete, the system was heated to 40 ° C and stirred for 1 h. After the system was cooled to room temperature, it was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x 2). The aqueous phase was adjusted to pH ~ 9 with sodium bicarbonate, and then extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 45-3, which was directly used in the next step without further purification.

¹ H NMR (400MHz, DMSO-d ₆ ) 11.98 (br s, 1H), 7.99 (d, J = 1.5Hz, 1H), 7.52-7.43 (m, 1H), 7.05-6.89 (m, 4H), 6.83 (d,J=8.5Hz,2H),5.69-5.06(m,2H),3.72-3.63(m,6H).

MS (ESI) m/z (M+Na) ⁺ = 524.9.

Step 4: Preparation of compound 45-4

Compound 45-3 (2.94 g, 5.85 mmol) and N,N-diisopropylethylamine (3.78 g, 29.23 mmol, 5.09 mL) were dissolved in acetonitrile (30 mL). Phosphorus oxychloride (3.59 g, 23.39 mmol, 2.17 mL) was added thereto at room temperature. After the addition, the system was heated to 80°C and stirred for 1 h. The system was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 45-4.

¹ H NMR (400MHz, DMSO-d ₆ )8.18(d,J＝1.4Hz,1H),7.58-7.53(m,1H),7.12(d,J＝8.6Hz,2H),7.07-6.95(m, 2H),6.90-6.84(m,2H),5.61-5.40(m,2H),3.72-3.66(m,6H).

MS (ESI) m/z (M+Na) ⁺ = 542.9.

Step 5: Preparation of compound 45-5

Compound 45-4 (1.6 g, 3.07 mmol), compound 1-11 (1.06 g, 4.60 mmol), N,N-diisopropylethylamine (1.19 g, 9.21 mmol, 1.60 mL) were dissolved in acetonitrile (30 mL), and the system was heated to 80 ° C and stirred for 3 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 45-5.

¹ H NMR (400MHz, DMSO-d ₆ )7.87(br s,1H),7.58-7.49(m,1H),7.09-6.94(m,4H),6.91-6.83(m,2H),5.58-5.31( m,2H),4.88-4.76(m,1H),4.29(br s,1H),4.09-3.96(m,1H),3.75-3.68(m,6H),3.64(s,2H),3.61-3.50 (m,2H),3.41(br s,1H),2.99(br s,1H),1.46-1.42(m,9H),1.25(d,J=6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 715.2.

Step 6: Preparation of compound 45-6

Compound 45-5 (1.56 g, 2.18 mmol) and Molecular sieves (0.6 g) were dissolved in N-methylpyrrolidone (15 mL), and a tetrahydrofuran solution of LiHMDS (1 M, 4.36 mL) was added thereto at room temperature. After the addition, the system was heated to 130 ° C and stirred for 12 h under a nitrogen atmosphere. The system was cooled to room temperature and filtered, and the filtrate was diluted with ethyl acetate (40 mL) and washed with saturated brine (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-60%) to obtain compound 45-6.

MS (ESI) m/z (M+H) ⁺ = 668.1.

Step 7: Preparation of compound 45-7

Compound 45-6 (0.56 g, 838.17 μmol) was dissolved in a mixed solvent of trifluoroacetic acid (7.70 g, 67.53 mmol, 5 mL) and anisole (2 mL). Trifluoromethanesulfonic acid (1.70 g, 11.33 mmol, 1 mL) was added thereto at room temperature (20°C). After the addition, the system was heated to room temperature (20°C) and stirred for 12 h under a nitrogen atmosphere. The system was concentrated, and the residue was poured into a mixture of ice water and a saturated sodium bicarbonate solution (adjusting pH to 7), extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (methanol/dichloromethane (v/v) = 0-30%) to obtain compound 45-7.

MS (ESI) m/z (M+H) ⁺ = 448.0.

Step 8: Preparation of compound 45-8

Compound 45-7 (0.35 g, 781.49 μmol) and triethylamine (158.16 mg, 1.56 mmol, 217.55 uL) were dissolved in dichloromethane (5 mL). Di-tert-butyl dicarbonate (341.12 mg, 1.56 mmol, 359.07 uL) was added at 0°C. After the addition, the system was heated to room temperature (20°C) and stirred for 12 hours. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-70%) to obtain compound 45-8.

¹ H NMR (400MHz, DMSO-d ₆ )12.00(s,1H),7.58-7.47(m,2H),7.08-6.95(m,2H),4.37-4.18(m,3H),3.95(br d, J＝14.9Hz,1H),3.77(d,J＝4.8Hz,3H),3.61(br s,2H),3.21(br s,1H),2.93(br d,J＝12.8Hz,1H),1.48 (br d,J＝6.7Hz,3H),1.46-1.43(m,1H),1.44(s,8H).

MS (ESI) m/z (M+Na) ⁺ = 570.0.

Step 9: Preparation of compound 45-10

Compound 45-9 (6 g, 52.10 mmol, 6.19 mL) was dissolved in chloroform (60 mL), and thionyl chloride (32.80 g, 275.70 mmol, 20.00 mL) was added dropwise at 0°C. After the addition, the system was heated to 65°C and stirred for 12 h under a nitrogen atmosphere. The system was concentrated to obtain compound 45-10, which was used directly in the next step without further purification.

Step 8: Preparation of compound 45-11

Compound 45-8 (120 mg, 218.99 μmol), compound 45-10 (74.49 mg, 437.97 μmol, HCl) and potassium carbonate (60.53 mg, 437.97 μmol) were dissolved in N,N-dimethylformamide (1 mL). After addition, the system was heated to 70 °C and stirred for 8 h. The system was concentrated, the residue was diluted with water (30 mL), extracted with ethyl acetate (25 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (methanol/dichloromethane (v/v) = 0-20%) and then purified by high performance preparative liquid phase (separation conditions: chromatographic column: Xtimate C18 100*30mm*3μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile%: 34%-54% 8min) to obtain compound 45-11.

MS (ESI) m/z (M+H) ⁺ = 645.4.

Step 9: Preparation of compound 45-12

Compound 45-11 (30 mg, 46.50 μmol) was dissolved in dichloromethane (1 mL), and a dichloromethane solution (0.3 mL) of boron tribromide (130 mg, 518.92 μmol, 0.05 mL) was added thereto. After the addition, the reaction was stirred at room temperature (25 ° C) for 4 h under a nitrogen atmosphere. The reaction solution was quenched with methanol (5 mL), and the system was concentrated to obtain compound 45-12, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 531.3.

Step 10: Preparation of compounds 45A and 45B

Compound 45-12 (30 mg, 56.50 μmol, HBr salt) was dissolved in tetrahydrofuran (2 mL) and saturated NaHCO ₃ aqueous solution (2.16 g, 25.71 mmol, 1 mL). A solution of acrylic anhydride (10 mg, 79.30 μmol) in tetrahydrofuran (0.3 mL) was added at room temperature (20 ° C). After the addition, the system was stirred at room temperature (20 ° C) for 2 h. Methanol (1 mL) and an aqueous solution of potassium carbonate (2M, 1 mL) were added to the system, and stirring was continued at room temperature (20 ° C) for 1.5 h. After the system was diluted with water (10 mL), the pH was adjusted to 6 with 1N hydrochloric acid, and extracted with ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile%: 40%-70% 9min) to obtain compounds 45A and 45B.

Compound 45A

¹ H NMR (400MHz, Methanol-d ₄ ) δ7.82 (br s, 1H), 7.39-7.25 (m, 1H), 6.86-6.65 (m, 3H), 6.26 (br d, J＝16.5Hz, 1H ),5.80(br d,J＝9.0Hz,1H),4.83-4.77(m,1H),4.61(br s,2H),4.54-4.07(m,3H),3.72(br s,1H),3.47 (br d,J＝12.3Hz,1H),3.38-3.35(m,1H),3.16(br s,1H),3.03(br s,1H),2.92(br s,1H),2.46(s,4H),1.84-1.58(m,7H).

MS (ESI) m/z (M+H) ⁺ = 585.3.

HPLC retention time: 3.744 min.

Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.2mL/1L ammonia solution)-acetonitrile; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 0.8mL/min.

Compound 45B

¹ H NMR (400MHz, Methanol-d ₄ ) δ7.82 (br s, 1H), 7.37-7.24 (m, 1H), 6.94-6.59 (m, 3H), 6.26 (br dd, J＝1.8, 16.8Hz ,1H),5.81(br s,1H),4.82-4.57(m,3H),4.56-4.34(m,2H),4.23-4.06(m,1H),3.70(br d,J＝16.1Hz,1H ),3.48(br d,J＝11.5Hz,1H),3.44-3.35(m,1H),3.17(br s,1H),3.02(br s,1H),2.91(br s,1H),2.64-2.20(m,4H),2.09-1.37(m,7H).

MS (ESI) m/z (M+H) ⁺ = 585.3.

HPLC retention time: 3.836 min.

Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.2mL/1L ammonia solution)-acetonitrile; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 0.8mL/min.

Example 46: Preparation of Compound 46

Step 1: Preparation of compound 46-1

Compound 28-4 (100 mg, 166.09 μmol), o-methoxyphenylboronic acid (68.15 mg, 249.14 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (13.89 mg, 16.61 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (7.75 mg, 16.61 μmol) and potassium carbonate (68.86 mg, 498.27 μmol) were dissolved in a mixed solution of dioxane (2 mL) and water (0.2 mL). Under a nitrogen atmosphere, the system was heated to 100 ° C and stirred for 5 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain compound 46-1.

MS (ESI) m/z (M+H) ⁺ = 694.7.

Step 2: Preparation of compound 46-2

Compound 46-1 (0.1 g, 148.42 μmol) was dissolved in a dichloromethane solution of boron tribromide (1 M, 3 mL) and the reaction was stirred at room temperature (20°C) for 16 h. The reaction solution was quenched with methanol (1 mL) and stirred for 10 min. The system was concentrated to obtain compound 46-2, which was used directly in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 560.1.

Step 3: Preparation of compounds 46A and 46B

Compound 46-2 (95 mg, 145.14 μmol) was dissolved in ethyl acetate (2 mL) and saturated sodium bicarbonate aqueous solution (4.10 g, 48.79 mmol, 1.90 mL), and a tetrahydrofuran solution of acrylic anhydride (1 M, 145.14 uL) was added dropwise. After the addition was completed, the system was stirred at room temperature (20°C) for 1 h. The system was extracted with ethyl acetate (10 mL x 3), and the organic phases were combined and washed with water (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid phase (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30mm*3μm, mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile 36%-66% 9min) and then purified by SFC (separation conditions: chromatographic column Phenomenex-Cellulose-2 (250mm*30mm, 10μm), mobile phase: _CO2 -methanol (0.1% ammonia water); methanol 40%-40%) to obtain compounds 46A and 46B.

Compound 46A:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.49-8.38 (m, 1H), 7.65 (br d, J = 8.4Hz, 1H), 7.31-7.16 (m, 2H), 7.09 (br s, 2H ),6.90-6.76(m,2H),6.23(br d,J＝17.0Hz,1H),5.81(brdd,J＝1.9,10.7Hz,1H),4.82-4.68(m,2H),4.48(br s,1H),3.92(br d,J＝3.3Hz,2H),3.44(s,4H),2.89(br dd,J＝3.0,12.5Hz,1H),2.54(br d,J＝6.6Hz,1H),2.20(d,J＝6.2Hz,3H),1.67(br d,J＝6.6Hz,3H),1.29-0.92(m,6H).

MS (ESI) m/z (M+H) ⁺ = 614.3.

SFC retention time 5.221 min

Separation conditions: Chromatographic column: Cellulose 2 100 mm x 4.6 mm ID, 3 μm; Column temperature: 35° C.; Mobile phase: CO ₂ -methanol (0.05% DEA); Methanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL/min.

Compound 46B:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.43 (br d, J = 5.1 Hz, 1H), 7.66 ( br d, J = 6.6 Hz, 1H), 7.24 ( br d, J = 5.5 Hz, 2H ),7.17-6.97(m,2H),6.92-6.74(m,2H),6.23(br d,J＝18.7Hz,1H),5.81(br d,J＝12.6Hz,1H),4.80-4.55( m,3H),3.89(s,2H),3.43(s,4H),3.05-2.86(m,2H),1.98(s,3H),1.67(br d,J＝6.8Hz,3H),1.43- 0.99(m,6H).

MS (ESI) m/z (M+H) ⁺ = 614.3.

SFC retention time 5.904 min

Separation conditions: Chromatographic column: Cellulose 2 100 mm x 4.6 mm ID, 3 μm; Column temperature: 35° C.; Mobile phase: CO ₂ -methanol (0.05% DEA); Methanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL/min.

Example 47: Preparation of Compound 47

Step 1: Preparation of compound 47-1

Compound 32-2 (120 mg, 171.98 μmol) was dissolved in N,N-dimethylformamide (2 mL), and iodine (66 mg, 260.04 μmol) and potassium hydroxide (15 mg, 267.35 μmol) were added thereto. After the addition, the system was stirred at room temperature (20°C) for 1 h. Water (30 mL) and saturated sodium thiosulfate aqueous solution (1 mL) were added to the system, and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 47-1, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 824.1.

Step 2: Preparation of compound 47-2

Compound 47-1 (120 mg, 145.69 μmol) and cyclopropylboronic acid (40 mg, 465.67 μmol) were dissolved in a mixed solvent of toluene (5 mL) and water (0.5 mL), and tetrakistriphenylphosphine palladium (20 mg, 17.31 μmol) and potassium phosphate (93 mg, 438.13 μmol) were added thereto. After the addition, the system was heated to 100 ° C and stirred for 16 hours under a nitrogen atmosphere. The system was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (methanol/dichloromethane (v/v) = 0-7%) to obtain compound 47-2.

MS (ESI) m/z (M+H) ⁺ = 738.1.

Step 3: Preparation of compound 47-3

Compound 47-2 (120 mg, 162.64 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (770.00 mg, 6.75 mmol, 0.5 mL) was added thereto. After the addition, the reaction was stirred at room temperature (20°C) for 1 h. The system was concentrated to obtain compound 47-3, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 638.3.

Step 4: Preparation of compounds 47A, 47B, 47C and 47D

Compound 47-3 (120 mg, 159.63 μmol, trifluoroacetate) was dissolved in tetrahydrofuran (2 mL) and an aqueous solution of sodium bicarbonate (4.32 g, 51.42 mmol, 2.00 mL), and a tetrahydrofuran solution (0.5 mL) of acrylic anhydride (25.00 mg, 198.24 μmol) was added dropwise. After the addition was completed, the system was reacted at room temperature (20°C) for 2 h. The system was diluted with water (10 mL), and the pH was adjusted to 7 with 1N HCl. The product was extracted with ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid phase (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30mm*3μm, mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile 33%-63% 9min) and then purified by SFC (separation conditions: chromatographic column DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: _CO2 -ethanol (0.1% ammonia water); ethanol 55%-55%) to obtain compounds 47A, 47B, 47C and 47D.

Compound 47A:

¹ H NMR (400MHz, METHANOL-d ₄ ) δ8.41 (d, J = 5.1Hz, 1H), 7.75 (br d, J = 7.9Hz, 1H), 7.43 (d, J = 8.4Hz, 1H), 7.36-7.25(m,2H),7.13(dd,J＝11.0,17.0Hz,1H),6.25(br d,J＝16.8Hz,1H),5.87-5.73(m,1H),4.98-4.93(m ,1H),4.76(br d,J＝12.8Hz,1H),4.65-4.44(m,1H),4.05-3.88(m,2H),3.46(s,3H),2.94(br d,J＝12.8Hz,1H),2.76-2.62(m,1H),2.18(s,3H),2.10(s,3H),1.74-1.66(m,3H),1.14(br d,J＝6.6 Hz,3H),1.00(d,J＝6.6Hz,3H),0.89(br d,J＝7.3Hz,2H),0.69-0.56(m,2H),0.50-0.41(m,1H).

MS (ESI) m/z (M+H) ⁺ = 692.3.

SFC retention time: 5.462 min.

Separation conditions: Chromatographic column: Chiralpak IC-3 100×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 40%-40%; flow rate: 2.8 mL/min.

Compound 47B:

¹ H NMR (400MHz, METHANOL-d ₄ ) δ8.41(br d,J＝5.1Hz,1H),7.76(br d,J＝8.6Hz,1H),7.44(br d,J＝8.2Hz,1H ),7.31(br d,J＝8.6Hz,1H),7.22(br d,J＝4.9Hz,1H),7.13(br dd,J＝10.7,17.1Hz,1H),6.29-6.20(m,1H ),5.86-5.77(m,1H),5.00-4.94(m,1H),4.76(br d,J＝12.6Hz,1H),4.63-4.47(m,1H),4.02-3.87(m,2H),3.45(s,3H),3.05-2.91(m,2H),2.21-2.06(m, 3H),2.00(s,3H),1.78-1.64(m,3H),1.19(br dd,J＝6.7,14.0Hz,6H),0.90(br s,1H),0.69(br d,J＝2.6 Hz,2H),0.52(br d,J=8.6Hz,1H),0.42(br s,1H).

MS (ESI) m/z (M+H) ⁺ = 692.3.

SFC retention time: 4.669 min.

Separation conditions: Chromatographic column: Chiralpak IC-3 100×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 40%-40%; flow rate: 2.8 mL/min.

Compound 47C:

¹ H NMR (400MHz, METHANOL-d ₄ ) δ8.42(br d,J＝4.9Hz,1H),7.76(br d,J＝8.4Hz,1H),7.44(br d,J＝8.8Hz,1H ),7.31(br d,J＝8.6Hz,1H),7.25(br d,J＝4.9Hz,1H),7.13(br dd,J＝10.9,17.1Hz,1H),6.31-6.19(m,1H ),5.82(br d,J＝12.6Hz,1H),5.00-4.94(m,1H),4.76(br d,J＝14.6Hz,1H),4.63-4.49(m,1H),4.04-3.87(m,2H),3.45(s,3H),3.09-2.93(m,2H),2.19-2.03(m, 3H),1.98(s,3H),1.77-1.60(m,3H),1.29-1.04(m,6H),0.90(br s,1H),0.66(br s,2H),0.54-0.35(m, 2H).

MS (ESI) m/z (M+H) ⁺ = 692.3.

SFC retention time: 7.774 min.

Separation conditions: Chromatographic column: Chiralpak IC-3 100×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 40%-40%; flow rate: 2.8 mL/min.

Compound 47D:

¹ H NMR (400MHz, METHANOL-d ₄ ) δ8.41 (d, J = 4.9Hz, 1H), 7.76 (br d, J = 8.8Hz, 1H), 7.44 (d, J = 8.4Hz, 1H), 7.31(d,J＝8.6Hz,1H),7.25(d,J＝4.9Hz,1H),7.13(dd,J＝10.9,17.1Hz,1H),6.34-6.18(m,1H),5.88-5.76 (m,1H),5.01-4.95(m,1H),4.76(br d,J＝12.6Hz,1H),4.68-4.41(m,1H),4.08-3.84(m,2H),3.46(s,3H),3.07-2.90(m,1H),2.70-2.52(m, 1H),2.20(s,3H),2.12(s,3H),1.81-1.64(m,3H),1.17-0.99(m,6H),0.89(br d,J＝7.3Hz,1H),0.66( br s,2H),0.44(br dd,J＝3.1,7.9Hz,2H).

MS (ESI) m/z (M+H) ⁺ = 692.3.

SFC retention time: 6.286 min.

Separation conditions: Chromatographic column: Chiralpak IC-3 100×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 40%-40%; flow rate: 2.8 mL/min.

Example 48: Preparation of Compound 48

Step 1: Preparation of compound 48-1

Compound 24-1 (550 mg, 734.48 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.72 g, 15.04 mmol, 1.11 mL) was added, and the reaction was stirred at room temperature (20° C.) for 3 h. The reaction solution was concentrated to obtain compound 48-1, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 649.3.

Step 2: Preparation of compounds 48A and 48B

Compound 48-1 (200 mg, 308.30 μmol) was dissolved in tetrahydrofuran (2 mL) and saturated NaHCO ₃ aqueous solution (4.43 g, 52.73 mmol, 2.05 mL). Acrylic anhydride (77.76 mg, 616.60 μmol) was added at room temperature (25°C). After the addition, the system was stirred at room temperature (25°C) for 0.5 h. Water (10 mL) was added to the system for dilution, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-performance preparative liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile%: 52%-82% 9min) and then purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); mobile phase: [0.1% ammonia water isopropanol]; isopropanol%: 40%-40%) to obtain compounds 48A and 48B.

Compound 48A:

MS (ESI) m/z (M+H) ⁺ = 703.1.

SFC retention time 4.816 & 5.020 min.

Separation conditions: Chromatographic column: Chiralpak IG-3 100 mm x 4.6 mm ID, 3 μm; Column temperature: 40° C.; Mobile phase: CO ₂ -ethanol (0.05% DEA); Ethanol: 5%-40% 5.5 min, 5% 1.5 min; Flow rate: 2.5 mL/min.

Compound 48B:

MS (ESI) m/z (M+H) ⁺ = 703.1.

SFC retention time 3.769 & 4.831 min.

Separation conditions: Chromatographic column: Chiralpak IC-3 100 mm x 4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 40%-40%; flow rate: 2.8 mL/min.

Step 3: Preparation of compounds 48A-1 and 48A-2

The diastereoisomer compound 48A was purified by SFC (separation conditions: chromatographic column: DAICELCHIRALPAK IG (250 mm*30 mm, 10 μm); mobile phase: [CO ₂ -ethanol (0.1% ammonia water)]; ethanol%: 35%). After concentration, compound 48A-1 and compound 48A-2 were obtained.

Compound 48A-1:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.45 (d, J = 4.8Hz, 1H), 7.69 (br d, J = 7.8Hz, 1H), 7.48-7.39 (m, 1H), 7.28 (d ,J＝5.0Hz,1H),7.13(dd,J＝10.8,17.1Hz,1H),6.90(d,J＝8.5Hz,1H),6.85-6.75(m,1H),6.31-6.18(m, 1H),5.86-5.75(m,1H),4.94(br s,1H),4.75(br d,J＝13.3Hz,1H),4.61(br s,1H),4.40-4.26(m,2H),4.03-3.86(m,2H),3.68(s,3H),3.24-3.10(m,1H),2.66-2.50(m,2H),2.49- 2.38(m,1H),2.24-2.15(m,9H),1.76-1.64(m,3H),1.14(d,J＝6.8Hz,3H),1.06(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 703.3.

HPLC retention time 4.552 min.

Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5 μm, 2.1*50 mm; column temperature: 50° C.; mobile phase: water (0.2 mL/1 L NH ₃ H ₂ O)-acetonitrile; acetonitrile: 10%-80% for 6 min, 80% for 2 min; flow rate: 0.8 mL/min.

SFC retention time 4.846 min

Separation conditions: Chromatographic column: ChiralPak IG-3 100×4.6 mm ID, 3 μm; column temperature: 40° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% 5.5 min, 5% 1.5 min; flow rate: 2.5 mL/min.

Compound 48A-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.45 (d, J = 5.0Hz, 1H), 7.69 (br d, J = 8.8Hz, 1H), 7.49-7.38 (m, 1H), 7.28 (d ,J＝5.0Hz,1H),7.13(dd,J＝10.7,16.9Hz,1H),6.92(d,J＝8.5Hz,1H),6.85-6.74(m,1H),6.30-6.18(m, 1H),5.90-5.73(m,1H),4.94(br s,1H),4.75(br d,J＝13.3Hz,1H),4.68-4.47(m,1H),4.40-4.25(m,2H),4.02-3.86(m,2H),3.77(s,3H),3.26-3.10(m, 1H),2.65-2.49(m,2H),2.48-2.39(m,1H),2.28-2.10(m,9H),1.76-1.61(m,3H),1.12(d,J＝6.5Hz,3H) ,1.02(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 703.3.

HPLC retention time: 4.551 min.

Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5 μm, 2.1*50 mm; column temperature: 50° C.; mobile phase: water (0.2 mL/1 L NH ₃ H ₂ O)-acetonitrile; acetonitrile: 10%-80% for 6 min, 80% for 2 min; flow rate: 0.8 mL/min.

SFC retention time 5.054 min

Separation conditions: Chromatographic column: ChiralPak IG-3 100×4.6 mm ID, 3 μm; column temperature: 40° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% 5.5 min, 5% 1.5 min; flow rate: 2.5 mL/min.

Step 4: Preparation of compounds 48B-1 and 48B-2

The diastereoisomer compound 48B was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [CO ₂ -ethanol (0.1% ammonia water)]; ethanol%: 45%). After concentration, compound 48B-1 and compound 48B-2 were obtained.

Compound 48B-1:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.45 (d, J = 5.0Hz, 1H), 7.70 (br d, J = 9.3Hz, 1H), 7.49-7.38 (m, 1H), 7.25 (d ,J＝5.0Hz,1H),7.13(dd,J＝10.7,16.9Hz,1H),6.90(d,J＝8.5Hz,1H),6.86-6.76(m,1H),6.31-6.17(m, 1H),5.87-5.75(m,1H),4.94(br s,1H),4.74(br d,J＝12.5Hz,1H),4.66-4.43(m,1H),4.32(br t,J＝6.8Hz,2H),4.02-3.84(m,2H),3.72(s,3H),3.27-3.15(m,1H),2.95(td,J＝6.8,13.4Hz,1H),2.75 -2.61(m,1H),2.54(brdd,J＝6.3,12.0Hz,1H),2.30-2.18(m,6H),1.97(s,3H),1.75-1.65(m,3H),1.24(br d,J＝6.8Hz,3H),1.16(br d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 703.3.

HPLC retention time: 4.541 min.

Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; Column temperature: 50°C; Mobile phase: water (0.2mL/1L NH ₃ H ₂ O)-acetonitrile; Acetonitrile: 10%-80% 6min, 80% 2min; Flow rate: 0.8mL/min

SFC retention time 3.674 min

Separation conditions: Chromatographic column: Chiralpak IC-3 100×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 40%; flow rate: 2.8 mL/min.

Compound 48B-2:

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.46 (d, J = 5.0Hz, 1H), 7.70 (br d, J = 8.3Hz, 1H), 7.50-7.39 (m, 1H), 7.27 (d ,J＝4.8Hz,1H),7.14(dd,J＝10.8,16.8Hz,1H),6.92(d,J＝8.5Hz,1H),6.86-6.78(m,1H),6.32-6.17(m, 1H),5.86-5.73(m,1H),5.00-4.94(m,1H),4.75(br d,J＝13.1Hz,1H),4.67-4.49(m,1H),4.32(br t,J＝7.0Hz,2H),3.99-3.85(m,2H),3.75(s,3H),3.25-3.15(m,1H),2.97(td,J＝6.8,13.6Hz,1H),2.72 -2.56(m,1H),2.54-2.44(m,1H),2.27-2.15(m,6H),1.99(s,3H),1.76-1.62(m,3H),1.24(d,J＝6.8Hz ,3H),1.13(d,J＝6.8Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 703.3.

HPLC retention time 4.542 min.

Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; Column temperature: 50°C; Mobile phase: water (0.2mL/1L NH ₃ H ₂ O)-acetonitrile; Acetonitrile: 10%-80% 6min, 80% 2min; Flow rate: 0.8mL/min

SFC retention time: 4.668 min.

Separation conditions: Chromatographic column: Chiralpak IC-3 100×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 40%; flow rate: 2.8 mL/min.

Example 49: Preparation of Compound 49

Step 1: Preparation of compound 49-2

Compound 49-1 (16.4 g, 10 mmol), isopropenylboronic acid pinacol ester (20.2 g, 12 mmol) and sodium carbonate (31.8 g, 30 mmol) were dissolved in a mixed solvent of dioxane (200 mL) and water (50 mL). Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (7.3 g, 1 mmol) was added thereto. The reaction temperature was raised to 95°C and stirred for 16 h. The reaction solution was diluted with ethyl acetate (100 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 0-25%) to obtain compound 49-2.

¹ H NMR(400MHz,Chloroform-d)δ8.40(s,1H),5.70–5.58(m,1H),5.56–5.18(m,1H),4.52(brs,2H),2.18(s,3H) .

MS (ESI) m/z (M+H) ⁺ = 169.80.

Step 2: Preparation of compound 49-3

Compound 49-2 (8.4 g, 50 mmol), methylboric acid (15 g, 250 mmol) and cesium carbonate (66.5 g, 150 mmol) were dissolved in a mixed solvent of dioxane (100 mL) and water (25 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3.66 g, 5 mmol) was added thereto under nitrogen protection. The reaction temperature was raised to 100°C and stirred for 4 h. The reaction solution was diluted with ethyl acetate (100 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 0-25%) to obtain compound 49-3.

¹ H NMR(400MHz,Chloroform-d)δ8.55(s,1H),5.80–5.50(m,1H),5.50–5.33(m,1H),4.07(brs,2H),2.49(s,3H) ,2.17(s,3H).

MS (ESI) m/z (M+H) ⁺ = 150.00.

Step 3: Preparation of compound 49-4

Compound 49-3 (2.4 g, 16 mmol) was dissolved in methanol (80 mL), and palladium/carbon (700 mg) was added thereto under nitrogen protection. After the addition, the reaction was stirred at room temperature (20°C) for 3 h under a hydrogen atmosphere. The system was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 49-4, which was directly used in the next step without further purification.

MS(ESI) m/z(M+H) ⁺ =151.80.

Step 4: Preparation of compound 49-5

Under nitrogen protection, compound 18-8 (3.14 g, 7.2 mmol) and compound 49-4 (1.3 g, 8.6 mmol) were dissolved in toluene (20 mL), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (550 mg, 0.946 mmol), tris(dibenzylideneacetone)dipalladium (870 mg, 0.946 mmol) and cesium carbonate (7.04 g, 21.6 mmol) were added in sequence. After the addition, the reaction temperature was raised to 100 ° C and stirred for 16 h. The reaction solution was diluted with ethyl acetate (100 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 49-5.

¹ H NMR (400MHz, Chloroform-d) δ9.10 (s, 1H), 8.84 (d, J = 2.4Hz, 1H), 7.98 (dd, J = 1.7, 0.9Hz, 2H), 7.38–7.29 (m ,1H),6.84–6.67(m,2H),3.98(s,3H),3.74(d,J＝18.8Hz,3H),3.42(h,J＝6.8Hz,1H),2.41(d,J＝ 3.7Hz,3H),1.32–1.16(m,6H).

MS (ESI) m/z (M+H) ⁺ = 462.0.

Step 5: Preparation of compound 49-6

Compound 49-5 (2.1 g, 4.56 mmol) was dissolved in N,N-dimethylformamide (20 mL), and sodium hydride (910 mg, 22.8 mmol, 60%) was added thereto at 0°C. After the addition, the system was stirred at 0°C for 20 min. The system was warmed to room temperature (20°C), and acetyl chloride (1.6 mL, 22.8 mmol) was added thereto dropwise. After the addition was completed, the system was stirred at room temperature (20°C) for 1 h. Water (100 mL) was added to the system to quench, and the system was extracted with ethyl acetate (100 mL x 2), the organic phases were combined, concentrated, methanol (50 mL) and potassium carbonate (5 g) were added thereto, and the system was stirred at room temperature (20°C) for 1 h. The system was concentrated, water (50 mL) was added thereto for dilution, pH was adjusted to 7 with 1N HCl, extracted with ethyl acetate (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by reverse phase silica gel column chromatography (acetonitrile/water (0.5% ammonium bicarbonate aqueous solution) (v/v) = 5-95%) to obtain compound 49-6.

MS (ESI) m/z (M+H) ⁺ = 472.0.

Step 6: Preparation of compound 49-7

Under nitrogen protection, compound 49-6 (360 mg, 0.76 mmol) was dissolved in acetic acid (12 mL), and concentrated nitric acid (1.2 mL) was added thereto. After addition, the reaction was heated to 40 ° C and stirred for 2 h. The reaction solution was concentrated under reduced pressure to remove most of the acetic acid, poured into ice water, adjusted pH to 6 with sodium hydroxide, extracted with ethyl acetate (100 mL x 2), combined organic phases, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by reverse phase silica gel column chromatography (acetonitrile/water (0.5% ammonium bicarbonate aqueous solution) (v/v) = 5-95%) to obtain compound 49-7.

MS (ESI) m/z (M+H) ⁺ = 517.0.

Step 7: Preparation of compound 49-8

Under nitrogen protection, compound 49-7 (200 mg, 0.39 mmol) was dissolved in acetonitrile (6 mL), and diisopropylethylamine (0.8 mL) and phosphorus oxychloride (0.5 mL) were added thereto in sequence. After the addition, the reaction temperature was raised to 80 ° C and stirred for 2 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, poured into ice water, adjusted pH to 8 with sodium hydroxide, extracted with ethyl acetate (100 mL x 2), combined organic phases, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 0-35%) to obtain compound 49-8.

MS (ESI) m/z (M+H) ⁺ = 535.0.

Step 8: Preparation of compound 49-9

Compound 49-8 (112 mg, 0.2 mmol), compound 7-1 (57.2 mg, 0.22 mmol) and N,N-diisopropylethylamine (40 uL) were dissolved in acetonitrile (3 mL). Under closed conditions, the system was heated to 100 ° C and stirred for 4 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-35%) to obtain compound 49-9.

MS (ESI) m/z (M+H) ⁺ = 757.2.

Step 9: Preparation of compound 49-10

Compound 49-9 (282 mg, 0.37 mmol) and iron powder (280 mg, 5 mmol) were dissolved in acetic acid (15 mL), and the system was heated to 80 ° C and stirred for 45 min under a nitrogen atmosphere. The system was concentrated, diluted with dichloromethane (50 mL), and filtered. The filtrate was washed with a saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 49-10, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 695.2.

Step 10: Preparation of compound 49-11

Compound 49-10 (220 mg, 317 μmol) and potassium carbonate (100 mg, 799.6 μmol) were dissolved in acetone (10 mL). At room temperature (25°C), methyl iodide (200 uL) was added. After the addition, the system was heated to 60°C and stirred for 4 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-60%) to obtain compound 49-11.

MS (ESI) m/z (M+H) ⁺ = 709.2.

Step 11: Preparation of compounds 49-12 and 50-1

Compound 49-11 (100 mg, 141 μmol) was dissolved in dichloromethane (3 mL), and boron tribromide (1 mL) was added thereto, and the reaction was stirred at 25°C for 2 h. The reaction solution was quenched with methanol (10 mL), stirred for 10 min, and concentrated under reduced pressure to obtain a mixture of compound 49-12 (HBr salt) and 50-1 (hydrobromide salt), which was directly used in the next step without further purification.

Compound 49-12:

MS (ESI) m/z (M+H) ⁺ = 595.2.

Compound 50-1:

MS (ESI) m/z (M+H) ⁺ = 609.2.

Step 12: Preparation of compound 49

Compound 49-12 (100 mg, 0.168 mmol) was dissolved in dichloromethane (10 mL), the system was cooled to 0°C, triethylamine (0.3 mL, 2.1 mmol) and acryloyl chloride (27 mg, 0.3 mmol) were added dropwise, and the system was reacted at 0°C for 0.5 h. The system was quenched with methanol and concentrated to obtain a crude product. The crude product was dissolved in methanol (5 mL), potassium carbonate (140 mg) was added thereto, and after the addition was completed, the system was stirred at room temperature (20°C) for 30 min. The system was adjusted to pH ~ 6 with hydrochloric acid, and extracted with dichloromethane (20 mL) and water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by high-efficiency preparative liquid phase purification (separation conditions: chromatographic column Welch C18 21.2×250 mm, 10 μm; column temperature: 25° C.; mobile phase: water (10 mM/L NH ₄ HCO ₃ )-acetonitrile; acetonitrile 35%-75% 18 min; flow rate 30 mL/min) to obtain compounds 49A and 49B.

MS (ESI) m/z (M+H) ⁺ = 649.2.

Compound 49A:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.20 (brs, 1H), 8.97 (s, 1H), 7.82 (d, J = 1.5Hz, 1H), 7.21 (q, J = 7.9Hz, 1H) ,6.95(dd,J＝16.8,10.6Hz,0.7H),6.79(dd,J＝16.6,10.6Hz,0.3H),6.72–6.59(m,2H),6.08(dd,J＝16.8,2.4Hz ,1H),5.70(dd,J＝10.5,2.5Hz,1H),4.95(d,J＝14.0Hz,0.24H),4.81–4.69 (m,0.76H),4.54(d,J＝14.0Hz,0.74H),4.41–4.32(m,0.26H),4.00–3.86(m,1H),3.69(dd,J＝14.2,4.3Hz, 1H),3.30–3.20(m,4H),3.02–2.88(m,1H),2.72(dt,J＝12.5,4.2Hz,1H),2.01(d,J＝4.5Hz,3H),1.47(d ,J＝6.7Hz,3H),1.15–1.06(m,3H),1.04–0.94(m,3H).

MS (ESI) m/z (M+H) ⁺ = 649.2.

Compound 49B:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.16 (brs, 1H), 8.97 (s, 1H), 7.83 (s, 1H), 7.22 (d, J = 7.8Hz, 1H), 6.95 (dd, J＝16.8,10.6Hz,0.75H),6.79(dd,J＝16.5,10.6Hz,0.25H),6.77–6.48(m,2H),6.24–5.98(m,1H),5.76–5.50(m, 1H),4.95(d,J＝14.0Hz,0.25H),4.74(t,J＝5.2Hz, 0.75H),4.54(d,J＝14.1Hz,0.75H),4.38(s,0.25H),4.01–3.89(m,1H),3.69(dd,J＝14.1,4.3Hz,1H),3.25– 3.02(m,4H),2.88–2.65(m,1H),2.57–2.46(m,1H),2.25(s,3H),1.47(d,J＝6.8Hz,3H),0.97(d,J＝ 6.6Hz, 3H), 0.86 (d, J = 6.7Hz, 3H).

MS (ESI) m/z (M+H) ⁺ = 649.2.

Step 13: Separation of isomers of compound 49A

The diastereoisomer compound 49A was purified by SFC (separation conditions: column: ChiralCel OD, 250×30 mm I.D., 5 μm; mobile phase: [CO ₂ -ethanol (0.1% ammonia water)]; ethanol%: 30%-30%; flow rate: 70 mL/min). After concentration, compound 49A-1 and compound 49A-2 were obtained.

Compound 49A-1:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.18 (s, 1H), 8.97 (s, 1H), 8.18–7.75 (m, 1H), 7.21 (d, J = 7.7Hz, 1H), 6.95 ( dd,J＝16.8,10.6Hz,0.75H),6.79(dd,J＝16.5,10.6Hz,0.25H),6.72–6.60(m,2H),6.22–5.97(m,1H),5.81–5.60( m,1H),4.95(d,J＝13.9Hz,0.24H),4.74(d, J＝8.1Hz,0.74H),4.54(d,J＝14.0Hz,0.73H),4.37(s,0.23H),3.97–3.84(m,1H),3.69(dd,J＝14.2,4.3Hz, 1H),3.23–3.14(m,4H),3.01–2.82(m,1H),2.72(dd,J＝12.5,3.7Hz,1H),2.00(s,3H),1.47(d,J＝6.8Hz ,3H),1.17–0.91(m,6H).

MS (ESI) m/z (M+H) ⁺ = 649.0.

HPLC retention time: 5.345 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100 mm, 3.5 μm; column temperature: 40° C.; mobile phase: water (10 mM NH ₄ HCO ₃ )-acetonitrile; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL/min.

SFC retention time 4.426 min.

Separation conditions: Chromatographic column: Chiralcel OD-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min.

Compound 49A-2:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.18 (s, 1H), 8.97 (s, 1H), 8.18–7.75 (m, 1H), 7.21 (d, J = 7.7Hz, 1H), 6.95 ( dd,J＝16.8,10.6Hz,0.75H),6.79(dd,J＝16.5,10.6Hz,0.25H),6.72–6.60(m,2H),6.22–5.97(m,1H),5.81–5.60( m,1H),4.95(d,J＝13.9Hz,0.24H),4.74(d, J＝8.1Hz,0.74H),4.54(d,J＝14.0Hz,0.73H),4.37(s,0.23H),3.97–3.84(m,1H),3.69(dd,J＝14.2,4.3Hz, 1H),3.23–3.14(m,4H),3.01–2.82(m,1H),2.72(dd,J＝12.5,3.7Hz,1H),2.00(s,3H),1.47(d,J＝6.8Hz ,3H),1.17–0.91(m,6H).

MS (ESI) m/z (M+H) ⁺ = 649.2.

SFC retention time: 4.636 min.

Separation conditions: Chromatographic column: Chiralcel OD-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min.

Example 50: Preparation of Compound 50

Step 1: Preparation of compound 50

Compound 50-1 (100 mg, 0.168 mmol) was dissolved in dichloromethane (10 mL), the system was cooled to 0°C, triethylamine (0.3 mL, 2.1 mmol) and acryloyl chloride (27 mg, 0.3 mmol) were added dropwise, and the system was reacted at 0°C for 0.5 h. The system was quenched with methanol and concentrated to obtain a crude product. The crude product was dissolved in methanol (5 mL), potassium carbonate (140 mg) was added thereto, and after the addition was completed, the system was stirred at room temperature (20°C) for 30 min. The system was adjusted to pH ~ 6 with hydrochloric acid, and extracted with dichloromethane (20 mL) and water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by high-efficiency preparative liquid phase purification (separation conditions: chromatographic column Welch C18 21.2×250 mm, 10 μm; column temperature: 25° C.; mobile phase: water (10 mM/L NH ₄ HCO ₃ )-acetonitrile; acetonitrile 35%-75% 18 min; flow rate 30 mL/min) to obtain compound 50.

MS (ESI) m/z (M+H)+ = 663.0.

Step 2: Preparation of compounds 50A, 50B, 50C and 50D

The diastereoisomer compound 50 was purified by SFC (separation conditions: column: ChiralPakAD, 250×30 mm I.D., 10 μm; mobile phase: [CO ₂ -isopropanol (0.1% ammonia water)]; isopropanol%: 30%-30%; flow rate: 80 mL/min). After concentration, compounds 50A, 50B, 50C and 50D were obtained.

Compound 50A:

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.97 (s, 1H), 7.83 (d, J = 1.5Hz, 1H), 7.42 (td, J = 8.4, 7.0Hz, 1H), 7.02–6.90 ( m,2H),6.89–6.81(m,1H),6.16–6.03(m,1H),5.77–5.63(m,1H),4.95(d,J＝14.0Hz,0.25H),4.75(s,0.80 H),4.53(d,J=14. 0Hz,0.80H),4.42–4.35(m,0.23H),4.02–3.88(m,1H),3.74–3.65(m,4H),3.26–3.16(m,4H),2.75–2.56(m,2H ), 2.25 (d, J = 2.0Hz, 3H), 1.47 (d, J = 6.8Hz, 3H), 0.96 (d, J = 6.6Hz, 3H), 0.86 (d, J = 6.7Hz, 3H).

MS (ESI) m/z (M+H)+ = 663.2.

HPLC retention time: 6.258 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100mm, 3.5μm; Column temperature: 40°C; Mobile phase: water (10mM NH ₄ HCO ₃ )-acetonitrile; Acetonitrile: 5%-95% 7min; Flow rate: 1.2mL/min.

SFC retention time: 3.951 min.

Separation conditions: Chromatographic column: Chiralpak AD-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min.

Compound 50B:

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.10 (s, 1H), 8.02–7.91 (m, 1H), 7.55 (td, J = 8.5, 6.9Hz, 1H), 7.21–6.83 (m, 3H) ),6.29–6.12(m,1H),5.87–5.74(m,1H),5.08(d,J＝13.9Hz,0.25H),4.91–4.78(m,0.75H),4.67(d,J＝14.0 Hz,0.75H),4.55–4 .42(m,0.25H),4.18–4.00(m,1H),3.81(dd,J＝13.9,4.0Hz,1H),3.71(s,3H),3.43–3.25(m,4H),2.99– 2.62(m,2H),2.37(d,J＝1.8Hz,3H),1.59(d,J＝6.8Hz,3H),1.11(d,J＝6.6Hz,3H),1.04(d,J＝6.7 Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 663.2.

SFC retention time: 4.071 min.

Separation conditions: Chromatographic column: Chiralpak AD-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min.

Compound 50C:

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.97 (s, 1H), 7.83 (d, J = 1.5Hz, 1H), 7.43 (td, J = 8.5, 7.0Hz, 1H), 7.03–6.82 ( m,3H),6.16–6.00(m,1H),5.74–5.64(m,1H),4.95(d,J＝13.9Hz,0.25H),4.74(d,J＝7.9Hz,0.75H),4.54 (d,J＝14.1Hz,0.75H),4.45–4.31(m,0.2 5H),3.88(d,J＝3.8Hz,1H),3.68(dd,J＝14.2,4.2Hz,1H),3.61(s,3H),3.23–3.16(m,4H),2.92(p,J ＝6.7Hz,1H),2.72(dd,J＝12.4,3.6Hz,1H),2.00(s,3H),1.46(d,J＝6.8Hz,3H),1.08(d,J＝6.6Hz,3H ),1.01(d,J＝6.7Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 663.2.

HPLC retention time: 6.070 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100mm, 3.5μm; Column temperature: 40°C; Mobile phase: water (10mM NH ₄ HCO ₃ )-acetonitrile; Acetonitrile: 5%-95% 7min; Flow rate: 1.2mL/min.

SFC retention time: 5.963 min.

Separation conditions: Chromatographic column: Chiralpak AD-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min.

Compound 50D:

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.97 (s, 1H), 7.87–7.74 (m, 1H), 7.42 (td, J = 8.5, 6.9Hz, 1H), 7.06–6.81 (m, 3H) ),6.19–6.01(m,1H),5.75–5.62(m,1H),4.95(d,J＝14.0Hz,0.25H),4.80–4.70(m,0.75H),4.54(d,J＝14.1 Hz,0.75H),4. 41–4.33(m,0.25H),3.95–3.83(m,1H),3.76–3.62(m,4H),3.29–3.16(m,4H),2.94(p,J＝6.7Hz,1H),2.76 –2.57(m,1H),2.02(s,3H),1.46(d,J＝6.8Hz,3H),1.08(d,J＝6.6Hz,3H),0.97(d,J＝6.7Hz,3H) .

MS (ESI) m/z (M+H) ⁺ = 663.2.

HPLC retention time: 6.112 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100mm, 3.5μm; Column temperature: 40°C; Mobile phase: water (10mM NH ₄ HCO ₃ )-acetonitrile; Acetonitrile: 5%-95% 7min; Flow rate: 1.2mL/min.

SFC retention time: 7.041 min.

Separation conditions: Chromatographic column: Chiralpak AD-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min.

Example 51: Preparation of Compound 51

Step 1: Preparation of compound 51-1

Compound 15-2 (0.10 g, 0.175 mmol) and paraformaldehyde (50 mg, 1.66 mmol) were dissolved in N,N-dimethylformamide (2.0 mL). Potassium carbonate (0.05 g, 0.35 mmol) was added thereto at room temperature (25 ° C). After the addition, the system was heated to 80 ° C and stirred for 1 h. The system was cooled to room temperature, water (8 mL) was added thereto to quench the reaction, and ethyl acetate (2 mL x 2) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 51-1, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 601.0

Step 2: Preparation of compound 51-2

Compound 51-1 (75 mg, 0.125 mmol) and potassium carbonate (35 mg, 0.25 mmol) were dissolved in N,N-dimethylformamide (2 mL). At room temperature (25 ° C), iodomethane (53 mg, 0.375 mmol) was added thereto. After the addition, the system was stirred at room temperature (25 ° C) for 1 h under a nitrogen atmosphere. Water was added to the system to quench the reaction, and ethyl acetate (2 mL x 2) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-60%) to obtain compound 51-2.

MS (ESI) m/z (M+H) ⁺ = 615.2.

Step 3: Preparation of compound 51-3

Compound 51-2 (63 mg, 0.102 mmol), compound 2-3 (58.0 mg, 0.204 mmol), tetrakistriphenylphosphine palladium (30 mg, 0.025 mmol), potassium carbonate (29.0 mg, 0.204 mmol) were dissolved in a mixed solution of dioxane and water (2 mL, 3:1). Under a nitrogen atmosphere, the system was heated to 100 ° C and stirred for 1 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 51-3.

MS (ESI) m/z (M+H) ⁺ = 735.1.

Step 4: Preparation of compound 51-4

Compound 51-3 (55 mg, 0.075 mmol) was dissolved in a mixed solvent of hydrochloric acid (6N) and methanol (2 mL, 1:1). The system was heated to 55°C and reacted for 15 min. The system was concentrated to obtain a crude compound 51-4, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 591.0.

Step 5: Preparation of compound 51

Compound 51-4 (35 mg, 0.04 mmol) was dissolved in dichloromethane (3 mL), the system was cooled to 0°C, triethylamine (22.7 mg, 0.225 mmol) and acryloyl chloride (6.8 mg, 0.075 mmol) were added dropwise, and the system was reacted at 0°C for 0.5 h. The system was extracted with water (5 mL) and dichloromethane (3 mL), the organic phase was concentrated, the residue was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and water (1 mL), and lithium hydroxide (6 mg, 0.15 mmol) was added thereto. After the addition, the system was stirred at room temperature (25°C) for 30 min. The system was adjusted to pH ~ 6 with 1N HCl, extracted with dichloromethane (2 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column Welch C18 21.2×250 mm, 10 μm; mobile phase: water (10 mM/L NH ₄ HCO ₃ )-acetonitrile; acetonitrile: 20%-50% in 16 min; flow rate 30 mL/min) to obtain Compound 51A and Compound 51B.

Compound 51A:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.17(s,1H),8.45(s,1H),8.19–7.99(m,1H),7.25(s,2H),7.07–6.95(m,1H ),6.85–6.66(m,2H),6.12(d,J＝17.3Hz,1H),5.87–5.57(m,1H),5.41–5.18(m,2H),4. 73(d,J＝14.0Hz,1H),4.58–4.38(m,1H),3.62(d,J＝31.2Hz,2H),3.54–3.33(m,4H),2.87–2.65(m,1H) ,2.00(s,3H),1.32–1.22(m,3H),0.96(dd,J＝51.3,7.4Hz,6H).

MS (ESI) m/z (M+H) ⁺ = 645.40.

HPLC retention time 4.602 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100mm, 3.5μm; Column temperature: 40°C; Mobile phase: water (10mM NH ₄ HCO ₃ )-acetonitrile; Acetonitrile: 5%-95% 7min; Flow rate: 1.2mL/min.

Compound 51B:

MS (ESI) m/z (M+H) ⁺ = 645.40.

HPLC retention time: 4.566 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100mm, 3.5μm; Column temperature: 40°C; Mobile phase: water (10mM NH ₄ HCO ₃ )-acetonitrile; Acetonitrile: 5%-95% 7min; Flow rate: 1.2mL/min.

Example 52: Preparation of Compound 52

Step 18: Preparation of compound 52

Compound 8-16 (50 mg) was dissolved in dichloromethane (4 mL), and triethylamine (14 mg, 0.14 mmol) and propylenesulfonyl chloride (13 mg, 0.106 mmol) were added thereto at room temperature (20 ° C). After the addition, the system was stirred at room temperature (20 ° C) for 2 h. Tetrahydrofuran (4 mL) and water (1 mL) and an aqueous solution of lithium hydroxide (31.74 mg, 756.47 μmol) were added to the system, and stirring was continued at room temperature (20 ° C) for 2 h. The system was adjusted to a neutral pH with 1N hydrochloric acid, extracted with ethyl acetate (10 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column: Welch C18 21.2×250 mm, 10 μm; column temperature: 25°C; mobile phase: water (10 mM/L NH ₄ HCO ₃ )-acetonitrile; acetonitrile: 50%-70% 12 min; flow rate 30 mL/min) and then purified by SFC (separation conditions: chromatographic column: ChiralPak AD, 250×30 mm ID, 10 μm; mobile phase: [CO ₂ -isopropanol (0.1% ammonia water)]; isopropanol%: 35%-35%) to obtain compounds 52A and 52B.

Compound 52A:

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.88-9.80(m,1H),8.34-8.32(m,1H),7.93(s,1H),7.13-7.07(m,2H),6.89-6.81 (m,1H),6.62-6.53(m,2H),6.11-6.04(m,2H),4.05-3.95(m,1H),3.68-3.59(m,1H) ,3.53-3.43(m,2H),3.10-2.92(m,4H),2.60-2.54(m,1H),2.29-2.23(m,1H),1.73(m,3H),1.73-1.70(m, 3H),1.55-1.49(m,3H),1.00-0.98(m,3H),0.83-0.75(m,3H).

MS (ESI) m/z (M+H) ⁺ = 653.0.

HPLC 92% purity; retention time 5.876 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100mm, 3.5μm; Column temperature: 40°C; Mobile phase: water (10mM NH ₄ HCO ₃ )-acetonitrile; Acetonitrile: 5%-95% 7min; Flow rate: 1.2mL/min.

SFC retention time: 4.766 min.

Separation conditions: Chromatographic column: Chiralpak AD-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min.

Compound 52B:

. ¹ H NMR (400MHz, DMSO-d ₆ ) δ ¹ H NMR (400MHz, DMSO) 9.85. (b, 1H), 8.34-8.31 (m, 1H), 7.94 (s, 1H), 7.15-7.09 (m ,2H),6.88-6.82(m,1H),6.63-6.53(m,2H),6.13-6.04(m,2H),4.03-3.98(m,1H),3.66-3.60 (m,1H),3.52-3.04(m,2H),3.14-3.10(m,1H),3.05(s,3H),291-2.87(m,1H),2.29-2.25(m,2H),1.83 -1.78(m,3H),1.53-1.51(m,3H),0.96-0.94(m,3H),0.83-0.75(m,3H).

MS (ESI) m/z (M+H) ⁺ = 653.0.

HPLC 98% purity; retention time 5.930 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100mm, 3.5μm; Column temperature: 40°C; Mobile phase: water (10mM NH ₄ HCO ₃ )-acetonitrile; Acetonitrile: 5%-95% 7min; Flow rate: 1.2mL/min.

SFC retention time 5.380 min.

Separation conditions: Chromatographic column: Chiralpak AD-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min.

Example 53: Preparation of Compound 53

Step 1: Preparation of compound 53-2

Compound 53-1 (16.3 g, 100 mmol), isopropenylboronic acid pinacol ester (20.16 g, 120 mmol) and sodium carbonate (31.8 g, 300 mmol) were dissolved in a mixed solvent of dioxane (200 mL) and water (50 mL). [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (7.32 g, 10 mmol) was added thereto under nitrogen protection. The reaction temperature was raised to 95°C and stirred for 16 h. The reaction solution was diluted with ethyl acetate (100 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 0-25%) to obtain compound 53-2.

¹ H NMR (400MHz, Chloroform-d) δ7.76-7.75(m,1H),7.22-7.20(m,1H),5.47–5.46(m,1H),5.27–5.28(m,1H),5.17( brs,2H),2.06(s,3H).

MS (ESI) m/z (M+H) ⁺ = 168.80.

Step 2: Preparation of compound 53-3

Compound 53-2 (13.4 g, 80 mmol), ethylboric acid (29.52 g, 400 mmol) and cesium carbonate (104.32 g, 320 mmol) were dissolved in a mixed solvent of dioxane (200 mL) and water (50 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (5.85 g, 8 mmol) was added thereto under nitrogen protection. The reaction temperature was raised to 100°C and stirred for 4 h. The reaction solution was diluted with ethyl acetate (200 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 0-25%) to obtain compound 53-3.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.76 (d, J = 4.7Hz, 1H), 6.88 (d, J = 4.8Hz, 1H), 5.41 (t, J = 1.7Hz, 1H), 5.19 (dd,J＝2.0,1.0Hz,1H),4.72(brs,2H),2.62–2.43(m,2H),2.06(dd,J＝1.5,0.9Hz,3H),1.16(t,J＝7.4 Hz,3H).

.MS(ESI)m/z(M+H) ⁺ =162.8.

Step 3: Preparation of compound 53-4

Compound 53-3 (6.2 g, 38.3 mmol) was dissolved in methanol (100 mL), and palladium/carbon (700 mg) was added thereto under nitrogen protection. After the addition, the reaction was stirred at room temperature (20°C) for 3 h under a hydrogen atmosphere. The system was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 53-4, which was directly used in the next step without further purification.

.MS(ESI)m/z(M+H) ⁺ =165.0.

Step 4: Preparation of compound 53-5

Under nitrogen protection, compound 18-1 (2.78 g, 6.35 mmol) and compound 53-4 (1.3 g, 7.62 mmol) were dissolved in toluene (30 mL), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (404 mg, 0.7 mmol), tris(dibenzylideneacetone)dipalladium (640 mg, 0.7 mmol) and cesium carbonate (6.21 g, 19.05 mmol) were added in sequence. After the addition, the reaction temperature was raised to 100 ° C and stirred for 16 h. The reaction solution was diluted with ethyl acetate (100 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 0-50%) to obtain compound 53-5.

MS (ESI) m/z (M+H) ⁺ = 475.0.

Step 5: Preparation of compound 53-6

Compound 53-5 (3.2 g, 6.75 mmol) was dissolved in N,N-dimethylformamide (20 mL), and sodium hydride (1.35 g, 33.7 mmol, 60%) was added thereto at 0°C. After the addition, the system was stirred at 0°C for 20 min. The system was warmed to room temperature (20°C), and acetyl chloride (2.54 mL, 33.7 mmol) was added thereto dropwise. After the addition was completed, the system was stirred at room temperature (20°C) for 1 h. Water (100 mL) was added to the system to quench, and the system was extracted with ethyl acetate (100 mL x 2), the organic phases were combined, concentrated, methanol (50 mL) and potassium carbonate (5 g) were added thereto, and the system was stirred at room temperature (20°C) for 1 h. The system was concentrated, water (50 mL) was added thereto for dilution, the pH was adjusted to 7 with 1N HCl, extracted with ethyl acetate (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by reverse phase silica gel column chromatography (acetonitrile/water (0.5% ammonium bicarbonate aqueous solution) (v/v) = 5-95%) to obtain compound 53-6.

MS (ESI) m/z (M+H) ⁺ = 485.0.

Step 6: Preparation of compound 53-7

Under nitrogen protection, compound 53-6 (880 mg, 1.82 mmol) was dissolved in acetic acid (18 mL), and concentrated nitric acid (1.8 mL) was added thereto. After addition, the reaction temperature was raised to 40 ° C and stirred for 2 h. The reaction solution was concentrated under reduced pressure to remove most of the acetic acid, poured into ice water, and the pH was adjusted to 6 with sodium hydroxide. It was extracted with ethyl acetate (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by reverse phase silica gel column chromatography (acetonitrile/water (0.5% ammonium bicarbonate aqueous solution) (v/v) = 5-95%) to obtain compound 53-7.

MS (ESI) m/z (M+H) ⁺ = 530.0.

Step 7: Preparation of compound 53-8

Under nitrogen protection, compound 53-7 (200 mg, 0.378 mmol) was dissolved in acetonitrile (6 mL), and diisopropylethylamine (0.8 mL) and phosphorus oxychloride (0.5 mL) were added thereto in sequence. After the addition, the reaction temperature was raised to 80 ° C and stirred for 2 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, poured into ice water, adjusted to pH ~ 8 with sodium hydroxide, extracted with ethyl acetate (100 mL x 2), combined organic phases, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 0 ~ 35%) to obtain compound 53-8.

MS (ESI) m/z (M+H) ⁺ = 548.0.

Step 8: Preparation of compound 53-9

Compound 53-8 (140 mg, 0.306 mmol), compound 7-1 (102 mg, 0.398 mmol) and N,N-diisopropylethylamine (100 uL) were dissolved in acetonitrile (3 mL). Under closed conditions, the system was heated to 100 ° C and stirred for 4 hours. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-35%) to obtain compound 53-9.

MS (ESI) m/z (M+H) ⁺ = 770.2.

Step 9: Preparation of compound 53-10

Compound 53-9 (166 mg, 0.216 mmol) and iron powder (42 mg, 0.755 mmol) were dissolved in acetic acid (3 mL), and the system was heated to 80 ° C and stirred for 45 min under a nitrogen atmosphere. The system was concentrated, diluted with dichloromethane (50 mL), and filtered. The filtrate was washed with a saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 53-10, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 708.2.

Step 10: Preparation of compound 53-11

Compound 53-10 (148 mg, 210 μmol) and potassium carbonate (87 mg, 630 μmol) were dissolved in acetone (105 mL), and iodomethane (200 uL) was added thereto at room temperature (25°C). After the addition, the system was heated to 60°C and stirred for 4 hours under a nitrogen atmosphere. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-60%) to obtain compound 53-11.

Step 11: Preparation of compound 53-12

Compound 53-11 (140 mg, 194 μmol) was dissolved in dichloromethane (4 mL), and boron tribromide (1.5 mL) was added thereto, and the reaction was stirred at 25°C for 2 h. The reaction solution was quenched with methanol (10 mL), stirred for 10 min, and concentrated under reduced pressure to obtain compound 53-12 (HBr salt), which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 608.2.

Step 12: Preparation of compound 53

Compound 53-12 (140 mg, 0.231 mmol) was dissolved in dichloromethane (10 mL), the system was cooled to 0°C, triethylamine (0.3 mL, 0.462 mmol) and acryloyl chloride (27 mg, 0.3 mmol) were added dropwise, and the system was reacted at 0°C for 0.5 h. The system was quenched with methanol and concentrated to obtain a crude product. The crude product was dissolved in methanol (5 mL), potassium carbonate (140 mg) was added thereto, and after the addition was completed, the system was stirred at room temperature (20°C) for 30 min. The pH of the system was adjusted to 6 with hydrochloric acid, and the mixture was extracted with dichloromethane (20 mL) and water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid phase (separation conditions: chromatographic column Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile: 40%-70% for 12 min, flow rate: 30 mL/min) to obtain compounds 53A and 53B.

MS (ESI) m/z (M+H) ⁺ = 662.2.

Step 13: Separation of isomers of compound 53A

The diastereoisomer compound 53A was purified by SFC (separation conditions: chromatographic column: Phenomenex-Cellulose-2 (250mm*30mm, 10μm); mobile phase: [CO ₂ -isopropanol (0.1% ammonia water)]; isopropanol%: 30%-30%). After concentration, compound 53A-1 and compound 53A-2 were obtained.

Compound 53A-1:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.11 (brs, 1H), 8.45 (d, J = 5.0Hz, 1H), 7.81 (d, J = 1.5Hz, 1H), 7.19 (dd, J = 6.2,3.4Hz,2H),6.95(dd,J＝16.8,10.7Hz,0.75H),6.79(dd,J＝16.5,10.6Hz,0.25H),6.69–6.58(m,2H),6.20–6.01 (m,1H),5.75–5.63(m,1H),4.95(d,J＝14.0Hz,0.25H),4.76–4.69(m,0.75H ),4.53(d,J＝14.0Hz,0.75H),4.41–4.31(m,0.25H),4.02–3.87(m,1H),3.68(dd,J＝14.0,4.2Hz,1H),3.25– 3.18(m,4H),2.87–2.74(m,1H),2.74–2.53(m,1H),2.21–1.97(m,2H),1.46(d,J＝6.8Hz,3H),1.04(d, J＝6.6Hz, 3H), 0.96 (d, J＝6.7Hz, 3H), 0.91 (t, J＝7.6Hz, 3H).

MS (ESI) m/z (M+H) ⁺ = 662.2.

HPLC 92% purity; retention time 5.48 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100mm, 3.5μm; Column temperature: 40°C; Mobile phase: water (10mM NH ₄ HCO ₃ )-acetonitrile; Acetonitrile: 5%-95% 7min; Flow rate: 1.2mL/min.

SFC 90％ee.Retention time 4.24min

Separation conditions: Chromatographic column: Chiralpak AD-3150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min.

Compound 53A-2:

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.44 (d, J＝4.9Hz, 1H), 7.86–7.72 (m, 1H), 7.20 (d, J＝5.0Hz, 2H), 6.95 (dd, J＝16.8,10.6Hz,0.75H),6.79(dd,J＝16.7,10.3Hz,0.25H),6.69–6.50(m,2H),6.20–6.01(m,1H),5.75–5.60(m, 1H),4.95(d,J＝14.1Hz,0.25H), 4.79–4.65(m,0.75H),4.53(d,J＝14.0Hz,0.75H),4.40–4.28(m,0.25H),4.03–3.89(m,1H),3.68(dd,J＝14.2, 4.3Hz,1H),3.24–3.15(m,4H),2.89–2.56(m,2H),2.39–2.29(m,2H),1.46(d,J＝6.8Hz,3H),1.07–0.76(m ,9H).

MS (ESI) m/z (M+H) ⁺ = 662.2.

HPLC 98% purity; retention time 5.481 min

Separation conditions: Chromatographic column: Waters XBridge 4.6*100mm, 3.5μm; Column temperature: 40°C; Mobile phase: water (10mM NH ₄ HCO ₃ )-acetonitrile; Acetonitrile: 5%-95% 7min; Flow rate: 1.2mL/min.

SFC 100% ee. Retention time 4.643 min.

Separation conditions: Chromatographic column: Chiralpak AD-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min.

Step 7: Separation of isomers of compound 53B

The diastereoisomer compound 53B was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase: [CO ₂ -ethanol (0.1% ammonia water)]; ethanol%: 35%-35%). After concentration, compounds 53B-1 and 53B-2 were obtained.

Compound 53B-1:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.14 (s, 1H), 8.44 (d, J = 5.0Hz, 1H), 7.87–7.71 (m, 1H), 7.29–7.14 (m, 2H), 6.95(dd,J＝16.8,10.6Hz,0.75H),6.79(dd,J＝16.4,10.6Hz,0.25H),6.70–6.57(m,2H),6.19–6.00(m,1H),5.79– 5.57(m,1H),4.95(d,J＝13.7Hz,0.25H),4.79–4.69 (m,0.75H),4.53(d,J＝14.1Hz,0.75H),4.40–4.31(m,0.25H),4.02–3.85(m,1H),3.68(dd,J＝14.0,4.2Hz, 1H),3.25–3.15(m,4H),2.91–2.64(m,2H),2.23–1.94(m,2H),1.47(d,J＝6.9Hz,3H),1.02(dd,J＝17.9, 6.6Hz, 6H), 0.87 (t, J = 7.6Hz, 3H).

MS (ESI) m/z (M+H) ⁺ = 662.1.

HPLC 99% purity; retention time 5.78 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100mm, 3.5μm; Column temperature: 40°C; Mobile phase: water (10mM NH ₄ HCO ₃ )-acetonitrile; Acetonitrile: 5%-95% 7min; Flow rate: 1.2mL/min.

SFC 100% ee. Retention time 3.966 min.

Separation conditions: Chromatographic column: Chiralpak AD-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% for 5 min, 40% for 2.5 min, 5% for 2.5 min; flow rate: 2.5 mL/min.

Compound 53B-2:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.12 (brs, 1H), 8.45 (d, J = 5.0Hz, 1H), 7.87–7.66 (m, 1H), 7.26–7.14 (m, 2H), 6.96(dd,J＝16.8,10.6Hz,0.75H),6.79(dd,J＝16.6,10.7Hz,0.25H),6.68–6.53(m,2H),6.15–6.00(m,1H),5.77– 5.58(m,1H),4.95(d,J＝13.9Hz,0.25H),4.79–4.69(m,0.7 5H),4.53(d,J＝14.1Hz,0.75H),4.39–4.32(m,0.25H),4.02–3.93(m,1H),3.69(dd,J＝14.1,4.3Hz,1H),3.26 –3.16(m,4H),2.88–2.61(m,2H),2.41–2.26(m,2H),1.47(d,J＝6.8Hz,3H),1.00(t,J＝7.6Hz,3H), 0.95(d,J＝6.6Hz,3H),0.84(d,J＝6.7Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 662.1.

HPLC 99% purity; retention time 5.702 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100mm, 3.5μm; Column temperature: 40°C; Mobile phase: water (10mM NH ₄ HCO ₃ )-acetonitrile; Acetonitrile: 5%-95% 7min; Flow rate: 1.2mL/min.

SFC 100％ee. Retention time 4.777min

Separation conditions: Chromatographic column: Chiralpak AD-3 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% for 5 min, 40% for 2.5 min, 5% for 2.5 min; flow rate: 2.5 mL/min.

Example 54: Preparation of Compound 54

Step 1: Preparation of compound 54-1

Compound 53-10 (156 mg, 220 μmol), 2-chloro-N,N-dimethylethylamine hydrochloride (104 mg, 660 μmol), cesium carbonate (224 mg, 660 μmol) and potassium iodide (40 mg, 220 μmol) were dissolved in DMF (2 mL). Under nitrogen atmosphere, the system was heated to 120 ° C and stirred for 3 h. The system was poured into ice water and extracted with EA (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-90%) to obtain compound 54-1.

MS (ESI) m/z (M+H) ⁺ = 779.24.

Step 2: Preparation of compound 54-2

Compound 54-1 (115 mg, 148 μmol) was dissolved in dichloromethane (4 mL), and boron tribromide (1.5 mL) was added thereto, and the reaction was stirred at 25°C for 2 h. The reaction solution was quenched with methanol (10 mL), stirred for 10 min, and concentrated under reduced pressure to obtain compound 54-2 (HBr salt), which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 665.2.

Step 3: Preparation of Compounds 54A and 54B

Compound 54-2 (40 mg, 0.06 mmol) was dissolved in dichloromethane (10 mL), the system was cooled to 0°C, triethylamine (0.3 mL, 0.462 mmol) and acryloyl chloride (10 mg, 0.3 mmol) were added dropwise, and the system was reacted at 0°C for 0.5 h. The system was quenched with methanol and concentrated to obtain a crude product. The crude product was dissolved in methanol (5 mL), potassium carbonate (140 mg) was added thereto, and after the addition was completed, the system was stirred at room temperature (20°C) for 30 min. The system was adjusted to pH ~ 6 with hydrochloric acid, and extracted with dichloromethane (20 mL) and water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid phase (separation conditions: Welch C18 21.2×250 mm, 10 μm; column temperature: 25° C.; mobile phase: water (10 mM/L NH ₄ HCO ₃ )-acetonitrile; acetonitrile: 45%-65% 9 min, flow rate 30 mL/min) to obtain compounds 54A and 54B.

MS (ESI) m/z (M+H) ⁺ = 719.2.

Step 4: Separation of isomers of compound 54A

The diastereoisomer compound 54A was purified by SFC (separation conditions: chromatographic column: Phenomenex-Cellulose-2 (250mm*30mm, 10μm); mobile phase: [CO ₂ -isopropanol (0.1% ammonia water)]; isopropanol%: 30%-30%). After concentration, compound 54A-1 and compound 54A-2 were obtained.

Compound 54A-1:

MS (ESI) m/z (M+H) ⁺ = 719.0.

HPLC 92% purity; retention time 5.734 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100 mm, 3.5 μm; column temperature: 40° C.; mobile phase: water (10 mM NH ₄ HCO ₃ )-acetonitrile; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL/min.

SFC 90% ee. Retention time 4.098 min.

Separation conditions: Chromatographic column: ChiralPak AD, 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40%; flow rate: 2.5 mL/min.

Compound 54A-2:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.16 (brs, 1H), 8.45 (d, J = 4.9Hz, 1H), 7.95–7.63 (m, 1H), 7.33–7.14 (m, 2H), 6.96(dd,J＝16.8,10.6Hz,0.75H),6.85–6.73(m,0.25H),6.74–6.57(m,2H),6.07(dd,J＝16.9,2.2Hz,1H),5.82– 5.58(m,1H),4.95(d,J＝14.0Hz,0.25H),4.80–4.70(m,0.75H),4.53(d,J ＝14.1Hz,0.75H),4.43–4.33(m,0.25H),4.31–4.03(m,2H),3.99–3.85(m,1H),3.75–3.63(m,1H),3.24–3.15(m ,1H),2.83–2.71(m,1H),2.21–2.01(m,2H),1.99–1.80(m,6H),1.47(d,J＝6.8Hz,3H),1.05(d,J＝6.6 Hz,3H),1.00(d,J＝6.7Hz,3H),0.87(t,J＝7.6Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 719.0.

HPLC 98% purity; retention time 5.786 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100 mm, 3.5 μm; column temperature: 40° C.; mobile phase: water (10 mM NH ₄ HCO ₃ )-acetonitrile; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL/min.

SFC 100％ee. Retention time 4.706min

Separation conditions: Chromatographic column: ChiralPak AD, 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40%; flow rate: 2.5 mL/min.

Step 5: Separation of isomers of compound 54B

The diastereoisomer compound 54B was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: [CO ₂ -isopropanol (0.1% ammonia water)]; isopropanol%: 30%-30%). After concentration, compound 54B-1 and compound 54B-2 were obtained.

Compound 54B-1:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.12 (brs, 1H), 8.45 (d, J = 4.9Hz, 1H), 7.86–7.76 (m, 1H), 7.28–7.14 (m, 2H), 6.96(dd,J＝16.8,10.6Hz,0.75H),6.78(dd,J＝16.5,10.7Hz,0.25H),6.71–6.59(m,2H),6.07(dd,J＝16.9,2.6Hz, 1H),5.75–5.63(m,1H),4.94(d,J＝13.8Hz,0.25H),4.81–4.72(m,0.75H),4.53 (d,J＝14.0Hz,0.75H),4.40–4.33(m,0.25H),4.32–4.21(m,1H),4.21–4.11(m,1H),4.03–3.86(m,1H),3.68 (dd,J＝14.2,4.3Hz,1H),3.24–3.16(m,1H),3.01–2.90(m,1H),2.35–2.06(m,5H),2.01–1.90(m,6H),1.47 (d,J＝6.9Hz,3H),1.04–0.94(m,6H),0.91(d,J＝6.7Hz,3H).

MS (ESI) m/z (M+H) ⁺ = 719.0.

HPLC 98% purity; retention time 5.60 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100 mm, 3.5 μm; column temperature: 40° C.; mobile phase: water (10 mM NH ₄ HCO ₃ )-acetonitrile; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL/min.

SFC 100% ee. Retention time 4.845 min.

Separation conditions: Chromatographic column: ChiralPak AD-3, 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40%; flow rate: 2.5 mL/min.

Compound 54B-2:

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.45 (d, J＝5.0Hz, 1H), 7.82 (s, 1H), 7.19 (d, J＝5.0Hz, 2H), 6.96 (dd, J＝ 16.9,10.6Hz,0.75H),6.85–6.73(m,0.25H),6.67–6.50(m,2H),6.07(dd,J＝16.9,2.6Hz,1H),5.68(dd,J＝10.5, 2.4Hz,1H),4.94(d,J＝13.8Hz,0.25H),4.81–4.71(m,0.75H),4.53(d,J＝14. 0Hz,0.75H),4.41–4.35(m,0.25H),4.34–4.21(m,1H),4.17–4.05(m,1H),3.97–3.82(m,1H),3.72–3.57(m,1H ),3.04(d,J＝10.4Hz,1H),2.80–2.64(m,1H),2.27–2.05(m,5H),1.96(d,J＝9.6Hz,6H),1.46(d,J＝ 6.8Hz, 3H), 1.04 (d, J＝6.7Hz, 3H), 0.99–0.83 (m, 6H).

MS (ESI) m/z (M+H) ⁺ = 719.2.

HPLC 98% purity; retention time 5.587 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100 mm, 3.5 μm; column temperature: 40° C.; mobile phase: water (10 mM NH ₄ HCO ₃ )-acetonitrile; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL/min.

SFC 100％ee. Retention time 5.083min

Separation conditions: Chromatographic column: ChiralPak AD-3, 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -isopropanol (0.05% DEA); isopropanol: 5%-40%; flow rate: 2.5 mL/min.

Example 55: Preparation of Compound 55

Step 1: Preparation of compound 55

Compound 29-2 (25.0 mg, 0.039 mmol), 2-fluoroacrylic acid (3.5 mg, 0.039 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (22.0 mg, 0.059 mmol) and triethylamine (7.9 mg, 0.078 mmol) were dissolved in dichloromethane (1.5 mL), and the system was stirred at room temperature (25 ° C) for 2 h. Water (2 mL) was added to quench, and dichloromethane (1.5 mL x 2) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high performance preparative liquid chromatography (separation conditions: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile: 20%-40% 12 min, flow rate 30 mL/min), and then purified by SFC (separation conditions: chromatographic column: ChiralPak AD, 250×30 mm ID, 10 μm; mobile phase: [CO ₂ -ethanol (0.1% ammonia water)]; ethanol%: 20%-20%). After concentration, Compound 55A and Compound 55B were obtained.

Compound 55A:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.09 (d, J = 12Hz, 1H), 8.44 (d, J = 4Hz, 1H), 8.25 (s, 1H), 7.34-7.16 (m, 2H) ,6.77-6.59(m,2H),5.49-5.24(m,2H),4.79-4.58(m,2H),4.43-4.16(m,2H),4.07-3.96(m,2H),3.26-3.11( m,2H),2.39-2.19(m,2H),2.12-1.91(m,10H),1.72-1.50(m,3H),1.18-0.81(m,6H).

SFC retention time: 3.33 min.

Separation conditions: Chromatographic column: ChiralPak AD-3, 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min.

Compound 55B:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.12(d,J＝16Hz,1H),8.45(d,J＝4Hz,1H),8.27(s,1H),7.31-7.15(m,2H) ,6.76-6.61(m,2H),5.50-5.27(m,2H),4.76-4.56(m,2H),4.37-4.17(m,2H),4.08-3.83(m,4H),2.87-2.63( m,3H),2.43-2.14(m,6H),1.92-1.74(m,3H),1.69-1.51(m,3H),1.19-1.07(m,3H),1.05-0.97(m,3H).

SFC retention time: 3.81 min.

Separation conditions: Chromatographic column: ChiralPak AD-3, 150×4.6 mm ID, 3 μm; column temperature: 35° C.; mobile phase: CO ₂ -ethanol (0.05% DEA); ethanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min.

Example 56: Preparation of Compound 56

Step 1: Preparation of compound 56-1

Compound 25-2 (1.17 g, 2 mmol) and potassium carbonate (552 mg, 4 mmol) were dissolved in acetone (10 mL). At room temperature (20 ° C), iodomethane (2.84 g, 20 mmol) was added. After the addition, the system was stirred at room temperature 20 ° C for 2 h under nitrogen atmosphere. The system was concentrated to obtain a crude product. The crude product was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 601.0.

Step 2: Preparation of compound 56-3

Compound 56-1 (1.25 g, 2.08 mmol), compound 56-2 (1.22 g, 3.12 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (304 mg, 0.416 mmol), potassium phosphate (880 mg, 4.16 mmol) were dissolved in a mixed solution of dioxane (25 mL) and water (6 mL). Under a nitrogen atmosphere, the system was heated to 100 ° C and stirred for 6 hours. The system was concentrated and extracted with ethyl acetate (200 mL x 2) and water (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-70%) to obtain compound 56-3.

MS (ESI) m/z (M+H) ⁺ = 833.2.

Step 3: Preparation of compound 56-4

Compound 56-3 (200 mg, 0.240 mmol) was dissolved in a mixed solvent of methanol (2.6 mL) and tetrahydrofuran (3 mL). Hydrochloric acid/dioxane solution (3 mL) was added at 0°C. The system was heated to room temperature (25°C) and reacted for 10 min. The system was concentrated to obtain a crude compound 56-4, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 633.2.

Step 4: Preparation of compound 56-6

2-Methoxy-5-fluoro-aniline (23.12 g, 141.70 mmol, 19.11 mL) was dissolved in tetrahydrofuran (200 mL). At 5°C, a tetrahydrofuran solution (20 mL) of compound 56-5 (20 g, 141.70 mmol) was added thereto. The system was heated to room temperature (25°C) and reacted for 20 min. Sodium hydroxide aqueous solution (2M, 85.02 mL) was added to the system, and the system was heated to 80°C and reacted for 3 h. Water (200 mL) and tert-butyl methyl ether (500 mL) were added to the system, and the pH was adjusted to 5 with 1N hydrochloric acid. The system was separated and extracted, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. At 0°C, the crude product was slurried with petroleum ether (100 mL), filtered, and the filter cake was washed with petroleum ether (2x10 mL) and dried to obtain compound 56-6, which was directly used in the next step without further purification.

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 9.16 (s, 1H), 8.16 (br d, J = 10.8Hz, 1H), 8.01-7.37 (br, 2H), 7.03 (dd, J = 5.3, 9.0Hz, 1H), 6.91 (dt, J = 3.0, 8.5Hz, 1H), 3.83 (s, 3H).

Step 5: Preparation of compound 56-7

Compound 56-6 (26 g, 12.85 mmol) was dissolved in chloroform (500 mL) at 0-5°C, and liquid bromine (21.17 g, 132.45 mmol, 6.83 mL) was added thereto. The system was reacted at 0°C for 30 min, and then heated to 70°C for 2 h. The system was cooled to room temperature, filtered, and the filter cake was washed with chloroform (3 x 10 mL) and dried to obtain compound 56-7.

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 8.42 (br s, 1H), 7.06-6.87 (m, 2H), 3.87 (s, 3H).

Step 6: Preparation of compound 56-8

Compound 56-7 (36 g, 128.97 mmol, HBr salt) was dissolved in dichloromethane (500 mL), and boron tribromide (96.93 g, 386.92 mmol, 37.28 mL) was added dropwise at 0-10°C. After the addition was completed, the system was heated to room temperature (20°C) and reacted for 20 h. The system was cooled to 0°C, methanol (10 mL) was added dropwise to quench the reaction, the system was filtered, and the filter cake was washed with dichloromethane (10 mL x 2) and dried to obtain compound 56-8.

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 9.13-8.32 (br s, 4H), 6.89 (t, J = 9.0Hz, 1H), 6.74 (dd, J = 4.4, 8.8Hz, 1H)

Step 7: Preparation of compound 56-9

Compound 56-8 (15 g, 52.76 mmol) was dissolved in dioxane (150 mL), and di-tert-butyl dicarbonate (26.48 g, 121.35 mmol, 27.88 mL), 4-dimethylaminopyridine (322.28 mg, 2.64 mmol) and N,N-diisopropylethylamine (14.32 g, 110.80 mmol, 19.30 mL) were added thereto at 10-15 °C. After the addition, the system was heated to room temperature (20 °C) and reacted for 20 h. The system was concentrated, water (200 mL) was added thereto, and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain compound 56-9.

MS (ESI) m/z (M+1) ⁺ = 685.0

Step 8: Preparation of compound 56-10

Compound 56-9 (20 g, 52.03 mmol) was dissolved in methanol (15 mL), and sodium methoxide (4.22 g, 78.04 mmol) was added thereto at 10-15°C. After the addition, the system was heated to room temperature (20°C) and reacted for 20 h. The system was concentrated, water (200 mL) was added thereto, and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain compound 56-10.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 6.98-6.72 (m, 2H), 1.55 (s, 9H).

Step 8: Preparation of compound 56-11

Compound 56-10 (14 g, 49.24 mmol) was dissolved in pyridine (200 mL), and trifluoromethanesulfonic anhydride (16.67 g, 59.09 mmol, 9.75 mL) was added at 10°C. After the addition, the system was heated to room temperature (20°C) and reacted for 2 h. Water (200 mL) and 10% citric acid (100 mL) were added to the system, and extracted with dichloromethane (3x100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-15%) to obtain compound 56-11.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.99 (br s, 1H), 7.26-7.22 (m, 1H), 6.98 (t, J = 8.6Hz, 1H), 1.54 (s, 9H)

Step 9: Preparation of compound 56-2

Compound 56-11 (18 g, 43.23 mmol), bipyraclostrobin (65.87 g, 259.39 mmol), tetrakistriphenylphosphine palladium (5.00 g, 4.32 mmol), potassium acetate (12.73 g, 129.69 mmol) were dissolved in dioxane (200 mL). Under nitrogen atmosphere, the system was heated to 100 ° C and stirred for 20 h. The system was concentrated, and the residue was extracted with ethyl acetate (200 mL x 3) and water (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Acetone (500 mL), water (500 mL), ammonium acetate (105 g) and sodium periodate (250 g) were added thereto, and the system was reacted at room temperature (20 ° C) for 16 h. Ethyl acetate (500 mL) was added to the system, filtered, the filtrate was separated and extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was slurried with petroleum ether (100 mL) and filtered to obtain compound 56-2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 7.78-7.74 (m, 1H), 7.17-7.11 (m, 1H), 1.51 (s, 9H), 1.32 (s, 12H).

Step 10: Preparation of compound 56

Compound 56-4 (150 mg, 0.237 mmol) was dissolved in N,N-dimethylformamide (2 mL), and acrylic acid (25.6 mg, 0.356 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (135 mg, 0.356 mmol), and N,N-diisopropylethylamine (61 mg, 0.474 mmol) were added thereto, and the system was reacted at room temperature (25°C) for 2 h. The system was concentrated to obtain a crude product, which was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column Welch C18 21.2×250mm, 10μm; mobile phase: water (10mM/L ammonium bicarbonate)-acetonitrile; acetonitrile 50%-70% 12min; flow rate 30mL/min) and then purified by SFC (Cellulose-4, 250×30mm ID, 5μm; mobile phase: [CO ₂ -ethanol (0.1% ammonia water)]; ethanol%: 40%; flow rate: 80mL/min; column temperature: 38°C). After concentration, Compound 56A and Compound 56B were obtained.

Compound 56A

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.44-8.43(m,1H),8.19-8.17(m,1H),7.90-7.84(s,2H),7.24-7.23(m,1H),7.07 -6.82(m,3H),6.19-6.12(m,1H),5.78-5.72(m,1H),4.85-4.79(m,1H),4. 64-4.59(m,1H),4.60-3.59(m,1H),3.78-3.73(m,1H),3.31-3.20(m,4H),2.86-2.68(m,1H),2.33(s,1H ),1.99(s,3H),1.54-1.54(m,3H),1.05-1.03(m,6H).

MS (ESI) m/z (M+H) ⁺ = 687.2.

HPLC retention time: 5.619 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100mm, 3.5μm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile: 5%-95% 7min; flow rate: 1.2mL/min.

SFC retention time: 2.324 min.

Separation conditions: Chromatographic column: ChiralPak AD-3, 150×4.6 mm ID, 3 μm; Mobile phase: [CO ₂ -isopropanol (0.05% DEA)]; Isopropanol%: 5%-40% 5 min; Flow rate: 2.5 mL/min; Column temperature: 35°C.

Compound 56B

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.44-8.43(m,1H),8.18-8.16(m,1H),7.87(s,2H),7.24-7.22(m,1H,J＝Hz) ,7.06-6.94(m,3H),6.18-6.13(m,1H),5.78-5.75(m,1H),5.00-4.82(m,1H),4.64-4.60( m,1H),4.02-3.96(m,1H),3.78-3.75(m,1H),3.40-3.31(m,4H),2.89-2.86(m,1H),2.78-2.75(m,1H), 1.84(s,3H),1.57-1.52(m,3H),1.11-1.09(m,3H),0.97(m,3H).

MS (ESI) m/z (M+H) ⁺ = 687.2.

HPLC retention time: 5.516 min.

Separation conditions: Chromatographic column: Waters XBridge 4.6*100mm, 3.5μm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile: 5%-95% 7min; flow rate: 1.2mL/min.

SFC retention time: 3.063 min.

Separation conditions: Chromatographic column: ChiralPak AD-3, 150×4.6 mm ID, 3 μm; Mobile phase: [CO ₂ -isopropanol (0.05% DEA)]; Isopropanol%: 5%-40% 5 min; Flow rate: 2.5 mL/min; Column temperature: 35°C.

Example 57: Preparation of Compound 57

Step 1: Preparation of compound 57-1

Compound 23-2 (400 mg, 576.23 μmol) and potassium carbonate (318.56 mg, 2.30 mmol) were dissolved in N,N-dimethylformamide (2 mL). Compound 43-1 (466.96 mg, 1.73 mmol) and potassium iodide (95.65 mg, 576.23 μmol) were added thereto at room temperature (25 °C). After the addition, the system was heated to 100 °C and stirred for 16 h under a nitrogen atmosphere. The system was concentrated and extracted with ethyl acetate (10 mL x 2) and water (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1/7 to obtain compound 57-1.

MS (ESI) m/z (M+H) ⁺ = 883.4.

Step 2: Preparation of compound 57-2

Compound 57-1 (150 mg, 169.80 μmol) was dissolved in dichloromethane (6 mL). Palladium chloride (105.39 mg, 594.31 μmol) and triethylamine (429.56 mg, 4.25 mmol, 590.87 uL) were added thereto under a hydrogen atmosphere. The reaction was stirred at 25 ° C for 5 h under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1/7) to obtain compound 57-2.

MS (ESI) m/z (M+H) ⁺ = 749.4.

Step 3: Preparation of compound 57-3

Compound 57-2 (120 mg, 160.16 μmol) and sodium acetate (137 mg, 1.67 mmol) were dissolved in methanol (4 mL), and aqueous formaldehyde solution (872.00 mg, 10.74 mmol, 0.8 mL, 37% purity) was added thereto, and the reaction was stirred at 25°C for 0.5 h. A tetrahydrofuran solution (2 mL) of sodium cyanoborohydride (110 mg, 1.75 mmol) was added thereto, and the reaction was stirred at 25°C for 4 h. The reaction solution was diluted with ethyl acetate (40 mL), washed with saturated brine (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1/10 to obtain compound 57-3.

MS (ESI) m/z (M+H) ⁺ = 763.4.

Step 4: Preparation of compound 57-4

Compound 57-3 (80 mg, 104.81 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL) was added thereto. After the addition was completed, the system was stirred at room temperature (25°C) for 2 h. The system was concentrated, and the residue was dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate aqueous solution (10 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 57-4, which was directly used in the next step without further purification.

MS (ESI) m/z (M+H) ⁺ = 663.0.

Step 5: Preparation of compound 57

Compound 57-4 (50 mg, 75.40 μmol) was dissolved in dichloromethane (2 mL), and triethylamine (72.70 mg, 718.46 μmol, 0.1 mL) and acryloyl chloride (10.24 mg, 113.10 μmol, 9.23 uL) were added thereto at -40 °C. After the addition, the system was stirred at room temperature -40 °C for 30 min. Water (10 mL) was added to the system for dilution, and the system was extracted with dichloromethane (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column: Phenomenex Gemini-NX80*30 mm*3 μm; mobile phase: [water (10 mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile%: 48%-78% 9 min) to obtain compound 57.

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.44 (br d, J＝4.4Hz, 1H), 8.01 (br s, 1H), 7.48-7.35 (m, 1H), 7.25 (br dd, J＝ 4.9,16.6Hz,1H),7.07(dd,J＝10.7,16.8Hz,1H),6.94-6.85(m,1H),6.80(br t,J＝8.5Hz,1H),6.31-6.18(m, 1H),5.81(dd,J＝1.7,10.8Hz,1H),4.98(br s,1H),4.72(br d,J＝13.5Hz,1H),4.60(br s,2H),4.16-4.02(m,1H),3.99-3.80(m,2H),3.78-3.63(m,4H),3.43-3.35(m,1H),3.27-3.09(m,2H), 3.06-2.97(m,1H),2.34-2.19(m,3H),2.09-1.84(m,3H),1.77-1.60(m,3H),1.26-0.97(m,6H).MS(ESI)m /z(M+H) ⁺ =717.2.

HPLC retention time 4.512 min.

Separation conditions: Chromatographic column: Xbridge C18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.2mL/L ammonia)-acetonitrile; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 0.8mL/min.

Experimental Example 1: Inhibition of RAS-mediated signal transduction

The ability of the compounds disclosed herein to inhibit RAS-mediated signal transduction was evaluated and demonstrated as follows. NCI-H358 cells expressing mutant RAS (G12C) (ATCC catalog number CRL-5807) were cultured in RPMI medium containing 10% fetal bovine serum and penicillin/streptomycin double antibodies. The cells were plated in a 96-well plate (Corning catalog number 3699) at 40,000 cells per well and allowed to stand overnight to adhere to the bottom of the plate. The cells were treated with or without the compounds of the present invention (dimethyl sulfoxide, DMSO), and the final concentration of DMSO was ensured to be 0.5%. After 2 hours of treatment, the culture medium was removed, 4% paraformaldehyde (Beyotime catalog number E672002-0100) was added, and the cells were allowed to stand for 20 minutes. After the cells were fixed, they were washed with PBS and incubated with pre-cooled methanol for 10 minutes to permeabilize the cell membrane. 1X blocking buffer (Thermo catalog number 37520) was added and incubated for 1 hour to block nonspecific antibody binding.

Phosphorylated ERK levels were detected using an enzyme-linked immunosorbent assay (ELISA). Phosphorylated ERK antibody (CellSignal Technology catalog number 4370) was diluted 1:400 in 1X blocking buffer containing 0.05% Tween 20, added to a 96-well plate and incubated overnight at 4°C. The plate was washed five times with PBS containing 0.05% Tween 20. HRP-conjugated secondary antibody (Thermo catalog number 31460) was diluted 1:10,000 in 1X blocking buffer containing 0.05% Tween 20, added to a 96-well plate and incubated for 2 hours at room temperature. The plate was washed five times with PBS containing 0.05% Tween, TMB (Thermo catalog number 4816) was added and incubated at room temperature for 15 minutes. The reaction was stopped by adding 1 mol/L H2SO4, and the OD value was read at a wavelength of 450 nm using EnVision (PerkinElmer).

The total number of cells per well was determined using the Janus green staining method. After the phosphorylated ERK level was detected, the 96-well plate was washed with PBS until colorless, and 0.1% Janus green (Abcam catalog number ab111622) was added and incubated for 10 minutes. After washing with double distilled water, 0.1 mol/L HCl was added and incubated for 10 minutes with shaking. The OD value was read at a wavelength of 595 nm using EnVision (PerkinElmer).

The signal of pERK (Thr202/Tyr204) was normalized using the signal value of Janus Green, and the inhibition percentage after drug treatment relative to the DMSO reference was calculated. The percentage value was fitted by a four-parameter dose-response curve and the IC50 value was generated. The experimental results are shown in Table 1.

Table 1

The compounds of the present invention exhibit excellent ability to inhibit RAS-mediated signal transduction.

Experimental Example 2: Experiment on the ability to inhibit the growth of tumor cell lines expressing KRAS-G12C

The growth inhibition ability of the compounds of the present invention on cells expressing KRAS-G12C was evaluated by measuring cell viability and calculating GI50 value.

The tumor cell line NCI-H358 (ATCC catalog number CRL-5807) expresses KRAS-G12C and is cultured in RPMI medium supplemented with 10% fetal bovine serum and penicillin/streptomycin; the tumor cell line MIA PaCa2 (ATCC CRL-1420) expresses KRAS-G12C and is cultured in DMEM medium supplemented with 10% fetal bovine serum, 2.5% horse serum and penicillin/streptomycin.

The cells NCI-H358 and MIA-Paca2 were seeded in black transparent bottom 384-well plates (PerkinElmer catalog number 6007460) at a cell density of 1000 and 800, respectively, and the cells were allowed to adhere overnight (8-12 hours). After the cells adhered, the experimental group was added with a diluted compound of the present invention at a concentration of 5 times the working solution (the final concentration contained 0.1% dimethyl sulfoxide, i.e., DMSO); the control group was added with the same dilution as the experimental group (the final concentration contained 0.1% DMSO). After 72 hours, the ATP content was detected using the Cell Titer Glo reagent (Promega catalog number G7572) according to the instruction manual to determine the cell proliferation. The brief operating steps are: take out the cell plate and place it at room temperature for 30 minutes; add the Cell Titer Glo reagent of the same volume as the culture; place the culture plate on a shaker for 2 minutes of shaking and lysis; let the culture plate stand at room temperature for 10 minutes; and read the light signal value using the microplate reader EnVision (PerkinElmer).

The data of all experimental groups were used to calculate the inhibition percentage of each DMSO group, and the inhibition rate produced by 9 compound dose concentrations diluted at a 1/3 ratio was analyzed using the data processing software GraphPad to calculate the GI50. The experimental results are shown in Table 2.

Table 2

Experimental Example 3 Pharmacokinetic Experiment:

In this study, the pharmacokinetics of the drug were evaluated in mice by intravenous and oral administration.

Experimental methods and conditions: Male ICR mice were given a single dose of the test compound 1 mg/Kg (intravenous injection, solvent 5% DMSO + 15% Solutol + 80% saline) and 5 mg/Kg (oral administration, solvent 1% Tween80/2% HPMC/97% water), and blood was collected from the orbital vein at 5, 15, 30 min, 1, 2, 4, 6, 8, 24 hr after administration. Each sample was collected about 0.20 mL, and sodium heparin was used for anticoagulation. After collection, it was placed on ice and centrifuged within 1 hour to separate the plasma for testing. The blood drug concentration in plasma was detected by liquid phase tandem mass spectrometry (LC/MS/MS), and the measured concentration was used to calculate the pharmacokinetic parameters. The results are shown in Tables 17 and 18 below.

Table 17: Pharmacokinetics of intravenous administration (1 mg/kg)

Table 18: Pharmacokinetics of intragastric injection (5 mg/kg)

Compound T _1/2 (hr) C _max (ng/mL) AUC _inf (ng*hr/mL) F(%) AMG 510 0.57 177.00 155.14 17.61 Compound 3B-2 3.96 746.67 1984.18 17.01 Compound 29B 1.06 108.72 421.20 22.87 Compound 27C 1.78 133.67 526.88 20.30

Conclusion: It can be seen that the compounds of the present invention have good pharmacokinetic absorption in mice and have pharmacokinetic advantages.

Experimental Example 4 Xenotransplantation Experiment

Nu/Nu Nude female mice (n=7-10) were housed with five animals per cage and allowed free access to tap water and commercial mouse chow (Harlan Teklad 22/5 rodent diet-8640). Cell line xenograft experiments were performed and NCI-H358 tumors were grown in mice. Once the tumor size reached 300 mm ³ , animals were randomized and treated with vehicle control (1% Tween80 + 1% HPMC) or compound (doses: 10 mg/kg/day, 30 mg/kg/day, 100 mg/kg/day, respectively, orally). Tumor volume was calculated using the formula) 0.5×length×width×width. At the end of the experiment, animals were killed, tumors were harvested, weighed, and stored for additional analysis.

After administration of compound 29B, the changes in the body weight of mice are shown in FIG1 , and the changes in the tumor volume are shown in FIG2 .

Claims (27)

1. A compound represented by formula (I-B), its optical isomers and pharmaceutically acceptable salts thereof, in, R ₁ and R ₂ are independently selected from H, halogen and C _1-6 alkyl, and the C _1-6 alkyl is optionally substituted by 1, 2 or 3 R; R ₃ is selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 heteroalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl-O- and C _3-6 cycloalkyl-O-, wherein the C _1-6 alkyl, C _1-6 heteroalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl-O- or C _3-6 cycloalkyl-O- is optionally substituted with 1, 2 or 3 R; R ₄ is independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C 1-6 heteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl, _3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; R ₅ is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl-C _1-3 alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl-C _1-3 alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; L ₁ is selected from -C(=O)-, -S(=O)- and -S(=O) ₂ -; _R6 is selected from H, CN, _C1-6 alkyl, _C1-6 alkyl-S(=O) _2- , 3-6 membered heterocycloalkyl, _-C1-6 alkyl-3-6 membered heterocycloalkyl and _C3-6 cycloalkyl-C(=O)-, wherein the _C1-6 alkyl, _C1-6 alkyl-S(=O) _2- , 3-6 membered heterocycloalkyl, _-C1-6 alkyl-3-6 membered heterocycloalkyl or _C3-6 cycloalkyl-C(=O)- is optionally substituted by 1, 2 or 3 R; R ₇ is independently selected from H, halogen, OH, NH ₂ , CN, -C(＝O)-OH, C _1-6 alkyl-OC(＝O)-, -C(＝O)-NH ₂ , C _1-6 alkyl, C _1-6 heteroalkyl and -C _1-6 alkyl-3 to 6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _{1-6 heteroalkyl, C 1-6 alkyl} -OC(＝O)- or -C _1-6 alkyl-3 to 6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; T ₁ and T ₂ are independently selected from N and -C(R ₈ )-; R ₈ is selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C 1-6 heteroalkyl, C _3-6 cycloalkyl or _3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; R ₉ is selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl and C _1-6 heteroalkyl, wherein the C _1-6 alkyl or C _1-6 heteroalkyl is optionally substituted with 1, 2 or 3 R; R ₁₀ is selected from H, halogen, CN, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylamino, wherein any of the C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylamino Choose to be replaced by 1, 2 or 3 Rs; R is independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 heterocycloalkyl, C _3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, C _3-6 cycloalkyl-O- and 5- to 6-membered heterocycloalkyl-O-, wherein the C _1-6 alkyl, C _1-6 heterocycloalkyl, C _3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, C _3-6 cycloalkyl-O- or 5- to 6-membered heterocycloalkyl-O- is optionally substituted with 1, 2 or 3 R's; R' is selected from F, Cl, Br, I, OH, _NH2 and _CH3 ; Ring A is independently selected from C _6-10 aryl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl; n is selected from 0, 1, 2, 3 or 4; m is selected from 0, 1, 2, 3 or 4; D ₁ is selected from O; Y is selected from N, CH or C; for And when for When R ₂ and R ₁₀ do not exist; for when middle for When X ₁ and X ₂ are independently selected from -N＝, -C(R ₇ )＝ and -C(R ₇ ) ₂ -C(R ₇ )＝; when middle for when X ₁ and X ₂ are independently selected from a single bond, -O-, -S-, S(=O), S(=O) ₂ , -N(R ₆ )-, -C(=O)-, -C(R ₇ ) ₂ - and -C(R ₇ ) ₂ -C(R ₇ ) ₂ -; And, Y cannot connect two When the bond between Y and R ₉ is When , R ₉ does not exist; The above 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl or C _1-6 heterocycloalkyl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) ₂ - and N. 2. The compound represented by formula (I-A), its optical isomers and pharmaceutically acceptable salts thereof, in, R ₁ and R ₂ are independently selected from H, halogen and C _1-6 alkyl, and the C _1-6 alkyl is optionally substituted by 1, 2 or 3 R; R ₃ is selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 heteroalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl-O- and C _3-6 cycloalkyl-O-, wherein the C _1-6 alkyl, C _1-6 heteroalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl-O- or C _3-6 cycloalkyl-O- is optionally substituted with 1, 2 or 3 R; R ₄ is independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C 1-6 heteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl, _3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; R ₅ is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl-C _1-3 alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl-C _1-3 alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; L ₁ is selected from -C(=O)-, -S(=O)- and -S(=O) ₂ -; _R6 is selected from H, CN, _C1-6 alkyl, _C1-6 alkyl-S(=O) _2- , 3-6 membered heterocycloalkyl, _-C1-6 alkyl-3-6 membered heterocycloalkyl and _C3-6 cycloalkyl-C(=O)-, wherein the _C1-6 alkyl, _C1-6 alkyl-S(=O) _2- , 3-6 membered heterocycloalkyl, _-C1-6 alkyl-3-6 membered heterocycloalkyl or _C3-6 cycloalkyl-C(=O)- is optionally substituted by 1, 2 or 3 R; R ₇ is independently selected from H, halogen, OH, NH ₂ , CN, -C(＝O)OH, C _1-6 alkyl-OC(＝O)-, -C(＝O)-NH ₂ , C _1-6 alkyl, C _1-6 heteroalkyl and -C _1-6 alkyl-3～6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C 1-6 heteroalkyl, C _1-6 alkyl- _OC (＝O)- or -C _1-6 alkyl-3～6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; T ₁ and T ₂ are independently selected from N and -C(R ₈ )-; R ₈ is selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C 1-6 heteroalkyl, C _3-6 cycloalkyl or _3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; R is independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 heterocycloalkyl, C _3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, C _3-6 cycloalkyl-O- and 5- to 6-membered heterocycloalkyl-O-, wherein the C _1-6 alkyl, C _1-6 heterocycloalkyl, C _3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, C _3-6 cycloalkyl-O- or 5- to 6-membered heterocycloalkyl-O- is optionally substituted with 1, 2 or 3 R's; R' is selected from F, Cl, Br, I, OH, _NH2 and _CH3 ; Ring A is independently selected from C _6-10 aryl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl; n is selected from 0, 1, 2, 3 or 4; for And when for When , R ₂ does not exist; for when middle for When X ₁ and X ₂ are independently selected from -N＝, -C(R ₇ )＝ and -C(R ₇ ) ₂ -C(R ₇ )＝; when middle for when X ₁ and X ₂ are independently selected from a single bond, -O-, -S-, S(=O), S(=O) ₂ , -N(R ₆ )-, -C(=O)-, -C(R ₇ ) ₂ - and -C(R ₇ ) ₂ -C(R ₇ ) ₂ -; The above 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl or C _1-6 heterocycloalkyl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) ₂ - and N. 3. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, which are selected from in, X ₁ and X ₂ are each independently selected from a single bond, -O-, -S-, S(＝O), S(＝O) ₂ , -N(R ₆ )-, -C(＝O)-, -C(R ₇ ) ₂ - and -C(R ₇ ) ₂ -C(R ₇ ) ₂ -; R ₁ , R _{2 , R 3 ,} R ₄ , R ₅ , L ₁ , R ₆ , R ₇ , T ₁ , T ₂ , Ring A and n are as defined in claim 1 or 2. 4. The compound according to claim 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein R is independently selected from H, halogen, OH, _NH2 , CN, C _1-3 alkyl, C _1-3 alkoxy, C _{1-3 alkylthio, C 1-3} alkylamino, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C _3-6 cycloalkyl-O- and -5-6 membered heterocycloalkyl-O-, wherein the C _1-3 alkyl, C _1-3 alkoxy, _{C 1-3} alkylthio, C 1-3 alkylamino, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C _3-6 cycloalkyl-O- or 5-6 membered heterocycloalkyl-O- are optionally substituted by 1, ₂ or 3 R'. 5. The compound according to claim 4, its optical isomers and pharmaceutically acceptable salts thereof, wherein R is independently selected from H, F, Cl, Br, _I , OH, _NH2 , CN, Me, _CH2CH3 , 6. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein R ₁ and R ₂ are independently selected from H, F, Me, CF ₃ , 7. The compound according to claim 6, its optical isomers and pharmaceutically acceptable salts thereof, wherein the structural unit Selected from 8. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein _R3 is selected from H, halogen, OH, _NH2 , CN, _C1-3 alkyl, _C1-3 alkoxy, C1-3 alkylamino, _C1-3 alkylthio, 3-6 membered heterocycloalkyl, _C3-6 cycloalkyl, _3-6 membered heterocycloalkyl-O- and C3-6 cycloalkyl-O-, and the _C1-3 alkyl, _C1-3 alkoxy, _C1-3 alkylamino, _C1-3 alkylthio, _3-6 membered heterocycloalkyl, _C3-6 cycloalkyl, 3-6 membered heterocycloalkyl-O- or _C3-6 cycloalkyl-O- is optionally substituted by 1, 2 or 3 Rs. 9. The compound according to claim 8, its optical isomers and pharmaceutically acceptable salts thereof, wherein _R3 is selected from H, F, Cl, Br, I, OH, _NH2 , CN, Me, _CF3 , 10. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein _R4 is independently selected from H, halogen, OH, _NH2 , CN, _C1-3 alkyl, _C1-3 alkoxy, C1-3 alkylamino, C1-3 alkylthio, C3-6 cycloalkyl, _3-6 membered heterocycloalkyl, phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl and indolyl, and _{the C1-3} alkyl, _C1-3 alkoxy, _C1-3 alkylamino, C1-3 alkylthio, _C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl, _isothiazolyl , oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4 _- triazolyl, benzofuranyl, benzothienyl and indolyl. _3-6 -membered cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl or indolyl is optionally substituted by 1, 2 or 3 R. 11. The compound according to claim 10, its optical isomers and pharmaceutically acceptable salts thereof, wherein _R4 is selected from H, F, Cl, Br, I, OH, _NH2 , CN, Me, _CF3 , 12. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein ring A is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, 1H-benzo[d]imidazolyl, benzopyrazolyl, purinyl, quinolyl, isoquinolyl, isoquinolin-1(2H)-onyl, isoindolyl-1-onyl, benzo[d]oxazol-2(H)-onyl, benzo[d]oxazol-2(3H)-onyl, H-benzo[d][1,2,3]triazolyl, 1H-pyrazolo[3,4-b]pyridinyl, benzo[d]thiazolyl, and 1,3-dihydro-2H -benzo[d]imidazol-2-one, the phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, 1H-benzo[d]imidazolyl, benzopyrazolyl, purinyl, quinolyl, Isoquinolinyl, isoquinolin-1(2H)-onyl, isoindolyl-1-onyl, benzo[d]oxazol-2(H)-onyl, benzo[d]oxazol-2(3H)-onyl, H-benzo[d][1,2,3]triazolyl, 1H-pyrazolo[3,4-b]pyridinyl, benzo[d]thiazolyl or 1,3-dihydro-2H-benzo[d]imidazol-2-onyl is optionally substituted with 1, 2 or 3 R. 13. The compound according to claim 12, its optical isomers and pharmaceutically acceptable salts thereof, wherein the structural unit Selected from 14. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein _R5 is selected from H, _C1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, 5-6 membered heterocycloalkyl-C _1-3 alkyl-, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, purinyl, quinolyl, isoquinolyl, isoquinolin-1(2H)-onyl, isoindolyl-1-onyl, benzo[d]oxazol-2(H)-onyl and 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, the C _1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, 5-6 membered heterocycloalkyl-C _1-3 alkyl-, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, purinyl, quinolyl, isoquinolyl, isoquinolin-1(2H)-onyl, isoindolin-1-onyl, benzo[d]oxazol-2(H)-onyl or 1,3-dihydro-2H-benzo[d]imidazol-2-onyl is optionally substituted with 1, 2 or 3 R. 15. The compound according to claim 14, its optical isomers and pharmaceutically acceptable salts thereof, wherein R ₅ is selected from H, Me, 16. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein _R7 is independently selected from H, halogen, OH, _NH2 , CN, _C1-3 alkyl, _C1-3 alkyl-OC(＝O)-, -C(＝O) _-NH2 , _C1-3 alkoxy, _C1-3 alkylamino, _C1-3 alkylthio and _-C1-3 alkyl-3 to 6-membered heterocycloalkyl, and the _C1-3 alkyl, _C1-3 alkyl-OC(＝O)-, -C(＝O) _-NH2 , _C1-3 alkoxy, _C1-3 alkylamino, _C1-3 alkylthio or _-C1-3 alkyl-3 to 6-membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R. 17. The compound according to claim 16, its optical isomers and pharmaceutically acceptable salts thereof, wherein _R7 is independently selected from H, F, Cl, Br, I, OH, _NH2 , CN, Me, _CF3 , 18. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein _R6 is independently selected from H, CN, _C1-3 alkyl, _C1-3 alkyl-S(＝O) _2- , 3- to 6-membered heterocycloalkyl, _-C1-3 alkyl-3- to 6-membered heterocycloalkyl and _C3-6 cycloalkyl-C(＝O)-, and the _C1-3 alkyl, _C1-3 alkyl-S(＝O) _2- , 3- to 6-membered heterocycloalkyl, _-C1-3 alkyl 3- to 6-membered heterocycloalkyl or _C3-6 cycloalkyl-C(＝O)- is optionally substituted by 1, 2 or 3 Rs. 19. The compound according to claim 18, its optical isomers and pharmaceutically acceptable salts thereof, wherein R ₆ is independently selected from H, CN, Me, CF ₃ , 20. The compound according to claim 18, its optical isomers and pharmaceutically acceptable salts thereof, wherein _X1 and _X2 are independently selected from a single bond, _CH2 , _{CH2CH2 ,} C(=O), O, S, NH, N( _CH3 ), S(=O), S(=O) ₂ , 21. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein _R8 is selected from H, halogen, OH, _NH2 , CN, _C1-3 alkyl, _C1-3 alkoxy, C1-3 alkylamino and _C1-3 alkylthio, and _{the C1-3} alkyl, _C1-3 alkoxy, _C1-3 alkylamino or _C1-3 alkylthio is optionally substituted by 1, 2 or 3 Rs. 22. The compound according to claim 21, its optical isomers and pharmaceutically acceptable salts thereof, wherein _R8 is selected from H, F, Cl, Br, I, OH, _NH2 , CN, Me, _CF3 , 23. The compound according to claim 1, its optical isomers and pharmaceutically acceptable salts thereof, wherein the structural unit Selected from 24. The compound of the following formula, its optical isomers and pharmaceutically acceptable salts thereof: 25. A pharmaceutical composition comprising the compound according to any one of claims 1 to 24, its optical isomers and pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. 26. Use of the compound according to any one of claims 1 to 24, its optical isomers and pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 25 in the preparation of a medicament for preventing and/or treating a KRAS-G12C-related disease. 27. The use according to claim 26, wherein the KRAS-G12C related disease is selected from non-small cell lung cancer, colon cancer and pancreatic cancer.